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Genome polyprotein [Cleaved into: Core protein p21 (Capsid protein C) (p21); Core protein p19; Envelope glycoprotein E1 (gp32) (gp35); Envelope glycoprotein E2 (NS1) (gp68) (gp70); p7; Protease NS2-3 (p23) (EC 3.4.22.-); Serine protease NS3 (EC 3.4.21.98) (EC 3.6.1.15) (EC 3.6.4.13) (Hepacivirin) (NS3P) (p70); Non-structural protein 4A (NS4A) (p8); Non-structural protein 4B (NS4B) (p27); Non-structural protein 5A (NS5A) (p56); RNA-directed RNA polymerase (EC 2.7.7.48) (NS5B) (p68)]

 POLG_HCVBK              Reviewed;        3010 AA.
P26663;
01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
23-JAN-2007, sequence version 3.
12-AUG-2020, entry version 218.
RecName: Full=Genome polyprotein;
Contains:
RecName: Full=Core protein p21;
AltName: Full=Capsid protein C;
AltName: Full=p21;
Contains:
RecName: Full=Core protein p19;
Contains:
RecName: Full=Envelope glycoprotein E1;
AltName: Full=gp32;
AltName: Full=gp35;
Contains:
RecName: Full=Envelope glycoprotein E2;
AltName: Full=NS1;
AltName: Full=gp68;
AltName: Full=gp70;
Contains:
RecName: Full=p7;
Contains:
RecName: Full=Protease NS2-3;
Short=p23;
EC=3.4.22.-;
Contains:
RecName: Full=Serine protease NS3;
EC=3.4.21.98;
EC=3.6.1.15;
EC=3.6.4.13;
AltName: Full=Hepacivirin;
AltName: Full=NS3P;
AltName: Full=p70;
Contains:
RecName: Full=Non-structural protein 4A;
Short=NS4A;
AltName: Full=p8;
Contains:
RecName: Full=Non-structural protein 4B;
Short=NS4B;
AltName: Full=p27;
Contains:
RecName: Full=Non-structural protein 5A;
Short=NS5A;
AltName: Full=p56;
Contains:
RecName: Full=RNA-directed RNA polymerase;
EC=2.7.7.48;
AltName: Full=NS5B;
AltName: Full=p68;
Hepatitis C virus genotype 1b (isolate BK) (HCV).
Viruses; Riboviria; Flaviviridae; Hepacivirus.
NCBI_TaxID=11105;
NCBI_TaxID=9606; Homo sapiens (Human).
[1]
NUCLEOTIDE SEQUENCE [GENOMIC RNA].
PubMed=1847440;
Takamizawa A., Mori C., Fuke I., Manabe S., Murakami S., Fujita J.,
Onishi E., Andoh T., Yoshida I., Okayama H.;
"Structure and organization of the hepatitis C virus genome isolated from
human carriers.";
J. Virol. 65:1105-1113(1991).
[2]
PROTEIN SEQUENCE OF 1487-1500.
PubMed=8647104; DOI=10.1111/j.1432-1033.1996.0611p.x;
Borowski P., Heiland M., Oehlmann K., Becker B., Korneteky L.;
"Non-structural protein 3 of hepatitis C virus inhibits phosphorylation
mediated by cAMP-dependent protein kinase.";
Eur. J. Biochem. 237:611-618(1996).
[3]
SUBCELLULAR LOCATION, AND RNA-BINDING ACTIVITY OF CORE PROTEIN.
PubMed=8189501;
Santolini E., Migliaccio G., La Monica N.;
"Biosynthesis and biochemical properties of the hepatitis C virus core
protein.";
J. Virol. 68:3631-3641(1994).
[4]
CHARACTERIZATION OF PROTEASE NS2-3.
PubMed=9261354;
Pieroni L., Santolini E., Fipaldini C., Pacini L., Migliaccio G.,
La Monica N.;
"In vitro study of the NS2-3 protease of hepatitis C virus.";
J. Virol. 71:6373-6380(1997).
[5]
FUNCTION OF NS5A.
PubMed=9710605; DOI=10.1128/mcb.18.9.5208;
Gale M.J. Jr., Blakely C.M., Kwieciszewski B., Tan S.-L., Dossett M.,
Tang N.M., Korth M.J., Polyak S.J., Gretch D.R., Katze M.G.;
"Control of PKR protein kinase by hepatitis C virus nonstructural 5A
protein: molecular mechanisms of kinase regulation.";
Mol. Cell. Biol. 18:5208-5218(1998).
[6]
INTERACTION OF NS5A WITH HUMAN GRB2, AND MUTAGENESIS OF PRO-2322; PRO-2323
AND PRO-2326.
PubMed=10318918; DOI=10.1073/pnas.96.10.5533;
Tan S.-L., Nakao H., He Y., Vijaysri S., Neddermann P., Jacobs B.L.,
Mayer B.J., Katze M.G.;
"NS5A, a nonstructural protein of hepatitis C virus, binds growth factor
receptor-bound protein 2 adaptor protein in a Src homology 3 domain/ligand-
dependent manner and perturbs mitogenic signaling.";
Proc. Natl. Acad. Sci. U.S.A. 96:5533-5538(1999).
[7]
PHOSPHORYLATION AT SER-2194, AND MUTAGENESIS OF SER-2194.
PubMed=11118372; DOI=10.1006/viro.2000.0662;
Katze M.G., Kwieciszewski B., Goodlett D.R., Blakely C.M., Neddermann P.,
Tan S.-L., Aebersold R.;
"Ser(2194) is a highly conserved major phosphorylation site of the
hepatitis C virus nonstructural protein NS5A.";
Virology 278:501-513(2000).
[8]
CHARACTERIZATION OF PROTEASE NS2-3.
PubMed=11591719; DOI=10.1074/jbc.m108266200;
Thibeault D., Maurice R., Pilote L., Lamarre D., Pause A.;
"In vitro characterization of a purified NS2/3 protease variant of
hepatitis C virus.";
J. Biol. Chem. 276:46678-46684(2001).
[9]
INTERACTION OF NS5A WITH HUMAN PIK3R1.
PubMed=12186904; DOI=10.1128/jvi.76.18.9207-9217.2002;
He Y., Nakao H., Tan S.-L., Polyak S.J., Neddermann P., Vijaysri S.,
Jacobs B.L., Katze M.G.;
"Subversion of cell signaling pathways by hepatitis C virus nonstructural
5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-
kinase.";
J. Virol. 76:9207-9217(2002).
[10]
DOMAINS CD81-BINDING AND HVR2.
PubMed=12660945; DOI=10.1086/368221;
Hofmann W.P., Sarrazin C., Kronenberger B., Schonberger B., Bruch K.,
Zeuzem S.;
"Mutations within the CD81-binding sites and hypervariable region 2 of the
envelope 2 protein: correlation with treatment response in hepatitis C
virus-infected patients.";
J. Infect. Dis. 187:982-987(2003).
[11]
PHOSPHORYLATION OF NS5A.
PubMed=15016873; DOI=10.1128/jvi.78.7.3502-3513.2004;
Coito C., Diamond D.L., Neddermann P., Korth M.J., Katze M.G.;
"High-throughput screening of the yeast kinome: identification of human
serine/threonine protein kinases that phosphorylate the hepatitis C virus
NS5A protein.";
J. Virol. 78:3502-3513(2004).
[12]
DOMAINS ISDR AND V3 REGIONS.
PubMed=15258967; DOI=10.1002/jmv.20144;
Vuillermoz I., Khattab E., Sablon E., Ottevaere I., Durantel D., Vieux C.,
Trepo C., Zoulim F.;
"Genetic variability of hepatitis C virus in chronically infected patients
with viral breakthrough during interferon-ribavirin therapy.";
J. Med. Virol. 74:41-53(2004).
[13]
INTERACTION OF NS5A WITH CELLULAR PROTEINS.
PubMed=15607035; DOI=10.5483/bmbrep.2004.37.6.741;
Ahn J., Chung K.-S., Kim D.-U., Won M., Kim L., Kim K.-S., Nam M.,
Choi S.-J., Kim H.-C., Yoon M., Chae S.-K., Hoe K.-L.;
"Systematic identification of hepatocellular proteins interacting with NS5A
of the hepatitis C virus.";
J. Biochem. Mol. Biol. 37:741-748(2004).
[14]
INTERACTION OF NS5A WITH HUMAN BIN1, AND FUNCTION OF NS5A.
PubMed=16530520; DOI=10.1053/j.gastro.2005.12.030;
Nanda S.K., Herion D., Liang T.J.;
"The SH3 binding motif of HCV NS5A protein interacts with Bin1 and is
important for apoptosis and infectivity.";
Gastroenterology 130:794-809(2006).
[15]
SUBCELLULAR LOCATION OF CORE PROTEIN, AND FUNCTION OF CORE PROTEIN.
PubMed=17188392; DOI=10.1016/j.jhep.2006.10.019;
Jackel-Cram C., Babiuk L.A., Liu Q.;
"Up-regulation of fatty acid synthase promoter by hepatitis C virus core
protein: genotype-3a core has a stronger effect than genotype-1b core.";
J. Hepatol. 46:999-1008(2007).
[16]
REVIEW.
PubMed=10718937; DOI=10.1046/j.1365-2893.2000.00201.x;
McLauchlan J.;
"Properties of the hepatitis C virus core protein: a structural protein
that modulates cellular processes.";
J. Viral Hepat. 7:2-14(2000).
[17]
REVIEW, AND SUBCELLULAR LOCATION.
PubMed=14752815; DOI=10.1002/hep.20032;
Penin F., Dubuisson J., Rey F.A., Moradpour D., Pawlotsky J.-M.;
"Structural biology of hepatitis C virus.";
Hepatology 39:5-19(2004).
[18]
INTERACTION WITH HNRNPA1 AND SEPT6.
PubMed=17229681; DOI=10.1128/jvi.01311-06;
Kim C.S., Seol S.K., Song O.-K., Park J.H., Jang S.K.;
"An RNA-binding protein, hnRNP A1, and a scaffold protein, septin 6,
facilitate hepatitis C virus replication.";
J. Virol. 81:3852-3865(2007).
[19]
X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 1027-1215.
PubMed=8861916; DOI=10.1016/s0092-8674(00)81350-1;
Love R.A., Parge H.E., Wickersham J.A., Hostomsky Z., Habuka N.,
Moomaw E.W., Adachi T., Hostomska Z.;
"The crystal structure of hepatitis C virus NS3 proteinase reveals a
trypsin-like fold and a structural zinc binding site.";
Cell 87:331-342(1996).
[20]
X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1027-1206 AND 1678-1691.
PubMed=9568891; DOI=10.1002/pro.5560070402;
Yan Y., Li Y., Munshi S., Sardana V., Cole J.L., Sardana M.,
Steinkuehler C., Tomei L., de Francesco R., Kuo L.C., Chen Z.;
"Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a
2.2-A resolution structure in a hexagonal crystal form.";
Protein Sci. 7:837-847(1998).
[21]
X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1216-1650.
PubMed=9614113; DOI=10.1074/jbc.273.24.15045;
Cho H.-S., Ha N.-C., Kang L.-W., Chung K.M., Back S.H., Jang S.K.,
Oh B.-H.;
"Crystal structure of RNA helicase from genotype 1b hepatitis C virus. A
feasible mechanism of unwinding duplex RNA.";
J. Biol. Chem. 273:15045-15052(1998).
[22]
X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1013-1657.
PubMed=10574797; DOI=10.1016/s0969-2126(00)80025-8;
Yao N., Reichert P., Taremi S.S., Prosise W.W., Weber P.C.;
"Molecular views of viral polyprotein processing revealed by the crystal
structure of the hepatitis C virus bifunctional protease-helicase.";
Structure 7:1353-1363(1999).
[23]
STRUCTURE BY NMR OF 1027-1206.
PubMed=10366511; DOI=10.1006/jmbi.1999.2745;
Barbato G., Cicero D.O., Nardi M.C., Steinkuehler C., Cortese R.,
De Francesco R., Bazzo R.;
"The solution structure of the N-terminal proteinase domain of the
hepatitis C virus (HCV) NS3 protein provides new insights into its
activation and catalytic mechanism.";
J. Mol. Biol. 289:371-384(1999).
[24]
X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 2420-2950.
PubMed=10557268; DOI=10.1073/pnas.96.23.13034;
Bressanelli S., Tomei L., Roussel A., Incitti I., Vitale R.L., Mathieu M.,
De Francesco R., Rey F.A.;
"Crystal structure of the RNA-dependent RNA polymerase of hepatitis C
virus.";
Proc. Natl. Acad. Sci. U.S.A. 96:13034-13039(1999).
[25]
X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 2414-2989.
PubMed=10504728; DOI=10.1038/13305;
Lesburg C.A., Cable M.B., Ferrari E., Hong Z., Mannarino A.F., Weber P.C.;
"Crystal structure of the RNA-dependent RNA polymerase from hepatitis C
virus reveals a fully encircled active site.";
Nat. Struct. Biol. 6:937-943(1999).
[26]
X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 2420-2999.
PubMed=10574802; DOI=10.1016/s0969-2126(00)80031-3;
Ago H., Adachi T., Yoshida A., Yamamoto M., Habuka N., Yatsunami K.,
Miyano M.;
"Crystal structure of the RNA-dependent RNA polymerase of hepatitis C
virus.";
Structure 7:1417-1426(1999).
[27]
X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 2420-2955.
PubMed=11884572; DOI=10.1128/jvi.76.7.3482-3492.2002;
Bressanelli S., Tomei L., Rey F.A., De Francesco R.;
"Structural analysis of the hepatitis C virus RNA polymerase in complex
with ribonucleotides.";
J. Virol. 76:3482-3492(2002).
[28]
X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 2420-2989 IN COMPLEX WITH A
NON-NUCLEOSIDE INHIBITOR.
PubMed=12509436; DOI=10.1074/jbc.m209397200;
Wang M., Ng K.K.-S., Cherney M.M., Chan L., Yannopoulos C.G., Bedard J.,
Morin N., Nguyen-Ba N., Alaoui-Ismaili M.H., Bethell R.C., James M.N.G.;
"Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B
polymerase. Crystal structures and mechanism of inhibition.";
J. Biol. Chem. 278:9489-9495(2003).
[29]
X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 2420-2995 IN COMPLEX WITH AN
INHIBITOR.
PubMed=12805457; DOI=10.1128/jvi.77.13.7575-7581.2003;
Love R.A., Parge H.E., Yu X., Hickey M.J., Diehl W., Gao J., Wriggers H.,
Ekker A., Wang L., Thomson J.A., Dragovich P.S., Fuhrman S.A.;
"Crystallographic identification of a noncompetitive inhibitor binding site
on the hepatitis C virus NS5B RNA polymerase enzyme.";
J. Virol. 77:7575-7581(2003).
-!- FUNCTION: Core protein packages viral RNA to form a viral nucleocapsid,
and promotes virion budding. Modulates viral translation initiation by
interacting with HCV IRES and 40S ribosomal subunit. Also regulates
many host cellular functions such as signaling pathways and apoptosis.
Prevents the establishment of cellular antiviral state by blocking the
interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways
and by inducing human STAT1 degradation. Thought to play a role in
virus-mediated cell transformation leading to hepatocellular
carcinomas. Interacts with, and activates STAT3 leading to cellular
transformation. May repress the promoter of p53, and sequester CREB3
and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle
negative regulating factor CDKN1A, thereby interrupting an important
check point of normal cell cycle regulation. Targets transcription
factors involved in the regulation of inflammatory responses and in the
immune response: suppresses NK-kappaB activation, and activates AP-1.
Could mediate apoptotic pathways through association with TNF-type
receptors TNFRSF1A and LTBR, although its effect on death receptor-
induced apoptosis remains controversial. Enhances TRAIL mediated
apoptosis, suggesting that it might play a role in immune-mediated
liver cell injury. Seric core protein is able to bind C1QR1 at the T-
cell surface, resulting in down-regulation of T-lymphocytes
proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and
SV40 promoters. May suppress the human FOS and HIV-1 LTR activity.
Alters lipid metabolism by interacting with hepatocellular proteins
involved in lipid accumulation and storage. Core protein induces up-
regulation of FAS promoter activity, and thereby probably contributes
to the increased triglyceride accumulation in hepatocytes (steatosis)
(By similarity). {ECO:0000250}.
-!- FUNCTION: E1 and E2 glycoproteins form a heterodimer that is involved
in virus attachment to the host cell, virion internalization through
clathrin-dependent endocytosis and fusion with host membrane. E1/E2
heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but
this binding is not sufficient for infection, some additional liver
specific cofactors may be needed. The fusion function may possibly be
carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the
establishment of an antiviral state. E2 is a viral ligand for CD209/DC-
SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic
cells (DCs), and on liver sinusoidal endothelial cells and macrophage-
like cells of lymph node sinuses. These interactions allow capture of
circulating HCV particles by these cells and subsequent transmission to
permissive cells. DCs act as sentinels in various tissues where they
entrap pathogens and convey them to local lymphoid tissue or lymph node
for establishment of immunity. Capture of circulating HCV particles by
these SIGN+ cells may facilitate virus infection of proximal
hepatocytes and lymphocyte subpopulations and may be essential for the
establishment of persistent infection (By similarity). {ECO:0000250}.
-!- FUNCTION: P7 seems to be a heptameric ion channel protein (viroporin)
and is inhibited by the antiviral drug amantadine. Also inhibited by
long-alkyl-chain iminosugar derivatives. Essential for infectivity (By
similarity). {ECO:0000250}.
-!- FUNCTION: Protease NS2-3 is a cysteine protease responsible for the
autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation
following maturation (By similarity). {ECO:0000250}.
-!- FUNCTION: NS3 displays three enzymatic activities: serine protease,
NTPase and RNA helicase. NS3 serine protease, in association with NS4A,
is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and
NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human
IRF3, thus preventing the establishment of dsRNA induced antiviral
state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5'
direction, and likely RNA stable secondary structure in the template
strand. Cleaves and inhibits the host antiviral protein MAVS (By
similarity). {ECO:0000250}.
-!- FUNCTION: NS4B induces a specific membrane alteration that serves as a
scaffold for the virus replication complex. This membrane alteration
gives rise to the so-called ER-derived membranous web that contains the
replication complex (By similarity). {ECO:0000250}.
-!- FUNCTION: NS5A is a component of the replication complex involved in
RNA-binding. Its interaction with Human VAPB may target the viral
replication complex to vesicles. Down-regulates viral IRES translation
initiation. Mediates interferon resistance, presumably by interacting
with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by
interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A
is an inhibitor of viral replication (By similarity). {ECO:0000250}.
-!- FUNCTION: NS5B is an RNA-dependent RNA polymerase that plays an
essential role in the virus replication. {ECO:0000250}.
-!- CATALYTIC ACTIVITY:
Reaction=Hydrolysis of four peptide bonds in the viral precursor
polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr
in P1 and Ser or Ala in P1'.; EC=3.4.21.98;
-!- CATALYTIC ACTIVITY:
Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:11128, Rhea:RHEA-
COMP:11129, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:83400;
EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539};
-!- CATALYTIC ACTIVITY:
Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-
diphosphate + H(+) + phosphate; Xref=Rhea:RHEA:23680,
ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474,
ChEBI:CHEBI:57930, ChEBI:CHEBI:61557; EC=3.6.1.15;
-!- CATALYTIC ACTIVITY:
Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13;
-!- COFACTOR:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
Note=Binds 1 zinc ion per NS3 protease domain. {ECO:0000250};
-!- COFACTOR:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
Note=Binds 1 zinc ion per NS5A N-terminal domain. {ECO:0000250};
-!- ACTIVITY REGULATION: Activity of auto-protease NS2-3 is dependent on
zinc ions and completely inhibited by EDTA, 1,10-phenanthroline,
iodocetamide and N-ethylmaleimide. According to PubMed:9261354,
completely inhibited by the serine protease inhibitors TLCK and TPCK.
According to PubMed:8189501, almost completely inhibited by TPCK and
slightly inhibited by TLCK. Not inhibited by antipain, aprotinin, E64,
PMSF and pepstatin. Also inhibited by NS2-3 and NS4A derived peptides.
Serine protease NS3 is also activated by zinc ions.
-!- SUBUNIT: Core protein is a homomultimer that binds the C-terminal part
of E1 and interacts with numerous cellular proteins. Interaction with
human STAT1 SH2 domain seems to result in decreased STAT1
phosphorylation, leading to decreased IFN-stimulated gene
transcription. In addition to blocking the formation of phosphorylated
STAT1, the core protein also promotes ubiquitin-mediated proteasome-
dependent degradation of STAT1. Interacts with, and constitutively
activates human STAT3. Associates with human LTBR and TNFRSF1A
receptors and possibly induces apoptosis. Binds to human SP110 isoform
3/Sp110b, HNRPK, C1QR1, YWHAE, UBE3A/E6AP, DDX3X, APOA2 and RXRA
proteins. Interacts with human CREB3 nuclear transcription protein,
triggering cell transformation. May interact with human p53. Also binds
human cytokeratins KRT8, KRT18, KRT19 and VIM (vimentin). E1 and E2
glycoproteins form a heterodimer that binds to human LDLR, CLDN1, CD81
and SCARB1 receptors. E2 binds and inhibits human EIF2AK2/PKR. Also
binds human CD209/DC-SIGN and CLEC4M/DC-SIGNR. p7 forms a homoheptamer
in vitro. NS2 forms a homodimer containing a pair of composite active
sites at the dimerization interface. NS2 seems to interact with all
other non-structural (NS) proteins. NS4A interacts with NS3 serine
protease and stabilizes its folding. NS3-NS4A complex is essential for
the activation of the latter and allows membrane anchorage of NS3. NS3
interacts with human TANK-binding kinase TBK1 and MAVS. NS4B and NS5A
form homodimers and seem to interact with all other non-structural (NS)
proteins. NS5A also interacts with human EIF2AK2/PKR, FKBP8, GRB2,
BIN1, PIK3R1, SRCAP, VAPB and with most Src-family kinases. NS5B is a
homooligomer and interacts with human VAPB, HNRNPA1 and SEPT6 (By
similarity). {ECO:0000250}.
-!- SUBUNIT: [Non-structural protein 4B]: Interacts with host PLA2G4C; this
interaction likely initiates the recruitment of replication complexes
to lipid droplets. {ECO:0000250|UniProtKB:P27958}.
-!- INTERACTION:
P26663; P52480: Pkm; Xeno; NbExp=3; IntAct=EBI-6857429, EBI-647785;
P26663; Q62245: Sos1; Xeno; NbExp=2; IntAct=EBI-6857429, EBI-1693;
PRO_0000037536; PRO_0000037537 [P26663]: -; NbExp=6; IntAct=EBI-6838571, EBI-6838576;
PRO_0000037536; P04637: TP53; Xeno; NbExp=9; IntAct=EBI-6838571, EBI-366083;
PRO_0000037540; PRO_0000037540 [P26663]: -; NbExp=2; IntAct=EBI-6874437, EBI-6874437;
PRO_0000037540; PRO_0000037548 [Q9WMX2]; Xeno; NbExp=5; IntAct=EBI-6874437, EBI-6863741;
-!- SUBCELLULAR LOCATION: [Core protein p21]: Host endoplasmic reticulum
membrane; Single-pass membrane protein. Host mitochondrion membrane;
Single-pass type I membrane protein. Host lipid droplet. Note=The C-
terminal transmembrane domain of core protein p21 contains an ER signal
leading the nascent polyprotein to the ER membrane. Only a minor
proportion of core protein is present in the nucleus and an unknown
proportion is secreted.
-!- SUBCELLULAR LOCATION: [Core protein p19]: Virion {ECO:0000250}. Host
cytoplasm {ECO:0000250}. Host nucleus {ECO:0000250}. Secreted
{ECO:0000250}.
-!- SUBCELLULAR LOCATION: [Envelope glycoprotein E1]: Virion membrane
{ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host
endoplasmic reticulum membrane {ECO:0000250}; Single-pass type I
membrane protein {ECO:0000250}. Note=The C-terminal transmembrane
domain acts as a signal sequence and forms a hairpin structure before
cleavage by host signal peptidase. After cleavage, the membrane
sequence is retained at the C-terminus of the protein, serving as ER
membrane anchor. A reorientation of the second hydrophobic stretch
occurs after cleavage producing a single reoriented transmembrane
domain. These events explain the final topology of the protein. ER
retention of E1 is leaky and, in overexpression conditions, only a
small fraction reaches the plasma membrane.
-!- SUBCELLULAR LOCATION: [Envelope glycoprotein E2]: Virion membrane
{ECO:0000305}; Single-pass type I membrane protein {ECO:0000305}. Host
endoplasmic reticulum membrane {ECO:0000250}; Single-pass type I
membrane protein {ECO:0000250}. Note=The C-terminal transmembrane
domain acts as a signal sequence and forms a hairpin structure before
cleavage by host signal peptidase. After cleavage, the membrane
sequence is retained at the C-terminus of the protein, serving as ER
membrane anchor. A reorientation of the second hydrophobic stretch
occurs after cleavage producing a single reoriented transmembrane
domain. These events explain the final topology of the protein. ER
retention of E2 is leaky and, in overexpression conditions, only a
small fraction reaches the plasma membrane.
-!- SUBCELLULAR LOCATION: [p7]: Host endoplasmic reticulum membrane
{ECO:0000250}; Multi-pass membrane protein {ECO:0000250}. Host cell
membrane {ECO:0000250}. Note=The C-terminus of p7 membrane domain acts
as a signal sequence. After cleavage by host signal peptidase, the
membrane sequence is retained at the C-terminus of the protein, serving
as ER membrane anchor. Only a fraction localizes to the plasma
membrane.
-!- SUBCELLULAR LOCATION: [Protease NS2-3]: Host endoplasmic reticulum
membrane {ECO:0000305}; Multi-pass membrane protein {ECO:0000305}.
-!- SUBCELLULAR LOCATION: [Serine protease NS3]: Host endoplasmic reticulum
membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}.
Note=NS3 is associated to the ER membrane through its binding to NS4A.
-!- SUBCELLULAR LOCATION: [Non-structural protein 4A]: Host endoplasmic
reticulum membrane {ECO:0000305}; Single-pass type I membrane protein
{ECO:0000305}. Note=Host membrane insertion occurs after processing by
the NS3 protease.
-!- SUBCELLULAR LOCATION: [Non-structural protein 4B]: Host endoplasmic
reticulum membrane {ECO:0000250|UniProtKB:P27958}; Multi-pass membrane
protein {ECO:0000250|UniProtKB:P27958}. Host lipid droplet
{ECO:0000250|UniProtKB:P27958}.
-!- SUBCELLULAR LOCATION: [Non-structural protein 5A]: Host endoplasmic
reticulum membrane {ECO:0000250}; Peripheral membrane protein
{ECO:0000250}. Host cytoplasm, host perinuclear region {ECO:0000250}.
Host mitochondrion {ECO:0000250}. Note=Host membrane insertion occurs
after processing by the NS3 protease.
-!- SUBCELLULAR LOCATION: [RNA-directed RNA polymerase]: Host endoplasmic
reticulum membrane {ECO:0000305}; Single-pass type I membrane protein
{ECO:0000305}. Note=Host membrane insertion occurs after processing by
the NS3 protease.
-!- DOMAIN: The transmembrane regions of envelope E1 and E2 glycoproteins
are involved in heterodimer formation, ER localization, and assembly of
these proteins. Envelope E2 glycoprotein contain two highly variable
regions called hypervariable region 1 and 2 (HVR1 and HVR2). E2 also
contain two segments involved in CD81-binding. HVR1 is implicated in
the SCARB1-mediated cell entry. HVR2 and CD81-binding regions may be
involved in sensitivity and/or resistance to IFN-alpha therapy (By
similarity). {ECO:0000250}.
-!- DOMAIN: The N-terminus of NS5A acts as membrane anchor. The central
part of NS5A contains a variable region called interferon sensitivity
determining region (ISDR) and seems to be intrinsically disordered and
interacts with NS5B and host PKR (By similarity). The C-terminus of
NS5A contains a variable region called variable region 3 (V3). ISDR and
V3 may be involved in sensitivity and/or resistance to IFN-alpha
therapy. {ECO:0000250}.
-!- DOMAIN: The SH3-binding domain of NS5A is involved in the interaction
with human Bin1, GRB2 and Src-family kinases.
-!- DOMAIN: The N-terminal one-third of serine protease NS3 contains the
protease activity. This region contains a zinc atom that does not
belong to the active site, but may play a structural rather than a
catalytic role. This region is essential for the activity of protease
NS2-3, maybe by contributing to the folding of the latter. The helicase
activity is located in the C-terminus of NS3.
-!- PTM: Specific enzymatic cleavages in vivo yield mature proteins. The
structural proteins, core, E1, E2 and p7 are produced by proteolytic
processing by host signal peptidases. The core protein is synthesized
as a 21 kDa precursor which is retained in the ER membrane through the
hydrophobic signal peptide. Cleavage by the signal peptidase releases
the 19 kDa mature core protein. The other proteins (p7, NS2-3, NS3,
NS4A, NS4B, NS5A and NS5B) are cleaved by the viral proteases (By
similarity). {ECO:0000250}.
-!- PTM: Envelope E1 and E2 glycoproteins are highly N-glycosylated.
{ECO:0000250}.
-!- PTM: Core protein is phosphorylated by host PKC and PKA. {ECO:0000250}.
-!- PTM: NS5A is phosphorylated in a basal form termed p56. p58 is a
hyperphosphorylated form of p56. p56 and p58 coexist in the cell in
roughly equivalent amounts. Hyperphosphorylation is dependent on the
presence of NS4A. Human AKT1, RPS6KB1/p70S6K, MAP2K1/MEK1, MAP2K6/MKK6
and CSNK1A1/CKI-alpha kinases may be responsible for NS5A
phosphorylation. {ECO:0000269|PubMed:15016873}.
-!- PTM: NS4B is palmitoylated. This modification may play a role in its
polymerization or in protein-protein interactions (By similarity).
{ECO:0000250}.
-!- PTM: The N-terminus of a fraction of NS4B molecules seems to be
relocated post-translationally from the cytoplasm to the ER lumen, with
a 5th transmembrane segment. The C-terminus of NS2 may be lumenal with
a fourth transmembrane segment (By similarity). {ECO:0000250}.
-!- PTM: Core protein is ubiquitinated; mediated by UBE3A and leading to
core protein subsequent proteasomal degradation. {ECO:0000250}.
-!- MISCELLANEOUS: Cell culture adaptation of the virus leads to mutations
in NS5A, reducing its inhibitory effect on replication. {ECO:0000250}.
-!- MISCELLANEOUS: Core protein exerts viral interference on hepatitis B
virus when HCV and HBV coinfect the same cell, by suppressing HBV gene
expression, RNA encapsidation and budding. {ECO:0000250}.
-!- SIMILARITY: Belongs to the hepacivirus polyprotein family.
{ECO:0000305}.
-!- CAUTION: The core gene probably also codes for alternative reading
frame proteins (ARFPs). Many functions depicted for the core protein
might belong to the ARFPs. {ECO:0000305}.
-!- WEB RESOURCE: Name=Virus Pathogen Resource;
URL="https://www.viprbrc.org/brc/home.spg?decorator=flavi_hcv";
---------------------------------------------------------------------------
Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
Distributed under the Creative Commons Attribution (CC BY 4.0) License
---------------------------------------------------------------------------
EMBL; M58335; AAA72945.1; -; Genomic_RNA.
PIR; A38465; GNWVTC.
PDB; 1A1Q; X-ray; 2.40 A; A/B/C=1027-1215.
PDB; 1BT7; NMR; -; A=1027-1206.
PDB; 1C2P; X-ray; 1.90 A; A/B=2422-2989.
PDB; 1CSJ; X-ray; 2.80 A; A/B=2420-2950.
PDB; 1CU1; X-ray; 2.50 A; A/B=1029-1657.
PDB; 1GX5; X-ray; 1.70 A; A=2420-2955.
PDB; 1GX6; X-ray; 1.85 A; A=2420-2950.
PDB; 1JXP; X-ray; 2.20 A; A/B=1027-1206, C/D=1678-1691.
PDB; 1NHU; X-ray; 2.00 A; A/B=2420-2989.
PDB; 1NHV; X-ray; 2.90 A; A/B=2420-2989.
PDB; 1NS3; X-ray; 2.80 A; A/B=1029-1206, C/D=1678-1689.
PDB; 1OS5; X-ray; 2.20 A; A=2420-2989.
PDB; 1QUV; X-ray; 2.50 A; A=2420-2989.
PDB; 2AWZ; X-ray; 2.15 A; A/B=2420-2989.
PDB; 2AX0; X-ray; 2.00 A; A/B=2420-2989.
PDB; 2AX1; X-ray; 2.10 A; A/B=2420-2989.
PDB; 2BRK; X-ray; 2.30 A; A=2420-2955.
PDB; 2BRL; X-ray; 2.40 A; A=2420-2955.
PDB; 2DXS; X-ray; 2.20 A; A/B=2420-2963.
PDB; 2GIQ; X-ray; 1.65 A; A/B=2421-2981.
PDB; 2GIR; X-ray; 1.90 A; A/B=2421-2981.
PDB; 2HAI; X-ray; 1.58 A; A=2420-2988.
PDB; 2HWH; X-ray; 2.30 A; A/B=2422-2989.
PDB; 2HWI; X-ray; 2.00 A; A/B=2422-2989.
PDB; 2I1R; X-ray; 2.20 A; A/B=2422-2989.
PDB; 2JC0; X-ray; 2.20 A; A/B=2420-2989.
PDB; 2JC1; X-ray; 2.00 A; A/B=2420-2989.
PDB; 2O5D; X-ray; 2.20 A; A/B=2422-2989.
PDB; 2WCX; X-ray; 2.00 A; A=2420-2955.
PDB; 2WHO; X-ray; 2.00 A; A/B=2420-2955.
PDB; 2WRM; X-ray; 1.95 A; A=2420-2955.
PDB; 2XWY; X-ray; 2.53 A; A=2420-2955.
PDB; 2ZKU; X-ray; 1.95 A; A/B/C/D=2420-2989.
PDB; 3BR9; X-ray; 2.30 A; A/B=2420-2989.
PDB; 3BSA; X-ray; 2.30 A; A/B=2420-2989.
PDB; 3BSC; X-ray; 2.65 A; A/B=2420-2989.
PDB; 3CDE; X-ray; 2.10 A; A/B=2420-2989.
PDB; 3CIZ; X-ray; 1.87 A; A/B=2421-2989.
PDB; 3CJ0; X-ray; 1.90 A; A/B=2421-2989.
PDB; 3CJ2; X-ray; 1.75 A; A/B=2421-2989.
PDB; 3CJ3; X-ray; 1.87 A; A/B=2421-2989.
PDB; 3CJ4; X-ray; 2.07 A; A/B=2421-2989.
PDB; 3CJ5; X-ray; 1.92 A; A/B=2421-2989.
PDB; 3CO9; X-ray; 2.10 A; A/B=2420-2989.
PDB; 3CVK; X-ray; 2.31 A; A/B=2420-2989.
PDB; 3CWJ; X-ray; 2.40 A; A/B=2420-2989.
PDB; 3D28; X-ray; 2.30 A; A/B=2420-2989.
PDB; 3D5M; X-ray; 2.20 A; A/B=2420-2989.
PDB; 3E51; X-ray; 1.90 A; A/B=2420-2989.
PDB; 3FQK; X-ray; 2.20 A; A/B=2421-2989.
PDB; 3FRZ; X-ray; 1.86 A; A=2420-2989.
PDB; 3G86; X-ray; 2.20 A; A/B=2421-2989.
PDB; 3GYN; X-ray; 2.15 A; A/B=2420-2989.
PDB; 3H2L; X-ray; 1.90 A; A/B=2420-2989.
PDB; 3H59; X-ray; 2.10 A; A/B=2421-2989.
PDB; 3H5S; X-ray; 2.00 A; A/B=2421-2989.
PDB; 3H5U; X-ray; 1.95 A; A/B=2421-2989.
PDB; 3H98; X-ray; 1.90 A; A/B=2421-2989.
PDB; 3IGV; X-ray; 2.60 A; A/B=2420-2989.
PDB; 3MF5; X-ray; 2.00 A; A/B=2421-2989.
PDB; 3RVB; X-ray; 2.20 A; A=1186-1657.
PDB; 3UA7; X-ray; 1.50 A; E/F=2321-2331.
PDB; 3UDL; X-ray; 2.17 A; A/B/C/D=2420-2989.
PDB; 3VQS; X-ray; 1.90 A; A/B/C/D=2420-2989.
PDB; 4A92; X-ray; 2.73 A; A/B=1029-1657, A/B=1678-1690.
PDB; 4B6E; X-ray; 2.46 A; A/B=1029-1657.
PDB; 4B6F; X-ray; 2.89 A; A/B=1029-1657.
PDB; 4B71; X-ray; 2.50 A; A/B=1029-1657.
PDB; 4B73; X-ray; 2.50 A; A/B=1029-1657.
PDB; 4B74; X-ray; 2.18 A; A/B=1029-1657.
PDB; 4B75; X-ray; 2.53 A; A/B=1029-1655.
PDB; 4B76; X-ray; 2.14 A; A/B=1029-1657.
PDB; 4DGV; X-ray; 1.80 A; A=412-423.
PDB; 4DGY; X-ray; 1.80 A; A=412-423.
PDB; 4EO6; X-ray; 1.79 A; A/B=2422-2989.
PDB; 4EO8; X-ray; 1.80 A; A/B=2422-2989.
PDB; 4IH5; X-ray; 1.90 A; A/B=2421-2989.
PDB; 4IH6; X-ray; 2.20 A; A/B=2421-2989.
PDB; 4IH7; X-ray; 2.30 A; A/B=2421-2989.
PDB; 4K8B; X-ray; 2.80 A; C/D=1678-1689.
PDB; 4KAI; X-ray; 2.30 A; A/B=2420-2989.
PDB; 4KB7; X-ray; 1.85 A; A/B=2420-2989.
PDB; 4KBI; X-ray; 2.06 A; A/B=2420-2989.
PDB; 4KE5; X-ray; 2.11 A; A/B=2420-2989.
PDB; 4MIA; X-ray; 2.80 A; A/B=2421-2989.
PDB; 4MIB; X-ray; 2.30 A; A/B=2421-2989.
PDB; 4MK7; X-ray; 2.80 A; A/B=2421-2989.
PDB; 4MK8; X-ray; 2.09 A; A/B=2421-2989.
PDB; 4MK9; X-ray; 2.05 A; A/B=2421-2989.
PDB; 4MKA; X-ray; 2.05 A; A/B=2421-2989.
PDB; 4MKB; X-ray; 1.90 A; A/B=2421-2989.
PDB; 4TN2; X-ray; 2.70 A; A=2422-2989.
PDB; 4WXP; X-ray; 2.08 A; A=1206-1656.
PDB; 5FPS; X-ray; 2.68 A; A/B=1029-1657.
PDB; 5FPT; X-ray; 2.72 A; A/B=1029-1657.
PDB; 5FPY; X-ray; 2.52 A; A/B=1029-1657.
PDB; 5KZP; X-ray; 2.26 A; A/B/C/D=412-423.
PDB; 5W2E; X-ray; 2.80 A; A/B=2422-2989.
PDB; 6MVP; X-ray; 2.00 A; A/B=2420-2989.
PDB; 8OHM; X-ray; 2.30 A; A=1216-1650.
PDBsum; 1A1Q; -.
PDBsum; 1BT7; -.
PDBsum; 1C2P; -.
PDBsum; 1CSJ; -.
PDBsum; 1CU1; -.
PDBsum; 1GX5; -.
PDBsum; 1GX6; -.
PDBsum; 1JXP; -.
PDBsum; 1NHU; -.
PDBsum; 1NHV; -.
PDBsum; 1NS3; -.
PDBsum; 1OS5; -.
PDBsum; 1QUV; -.
PDBsum; 2AWZ; -.
PDBsum; 2AX0; -.
PDBsum; 2AX1; -.
PDBsum; 2BRK; -.
PDBsum; 2BRL; -.
PDBsum; 2DXS; -.
PDBsum; 2GIQ; -.
PDBsum; 2GIR; -.
PDBsum; 2HAI; -.
PDBsum; 2HWH; -.
PDBsum; 2HWI; -.
PDBsum; 2I1R; -.
PDBsum; 2JC0; -.
PDBsum; 2JC1; -.
PDBsum; 2O5D; -.
PDBsum; 2WCX; -.
PDBsum; 2WHO; -.
PDBsum; 2WRM; -.
PDBsum; 2XWY; -.
PDBsum; 2ZKU; -.
PDBsum; 3BR9; -.
PDBsum; 3BSA; -.
PDBsum; 3BSC; -.
PDBsum; 3CDE; -.
PDBsum; 3CIZ; -.
PDBsum; 3CJ0; -.
PDBsum; 3CJ2; -.
PDBsum; 3CJ3; -.
PDBsum; 3CJ4; -.
PDBsum; 3CJ5; -.
PDBsum; 3CO9; -.
PDBsum; 3CVK; -.
PDBsum; 3CWJ; -.
PDBsum; 3D28; -.
PDBsum; 3D5M; -.
PDBsum; 3E51; -.
PDBsum; 3FQK; -.
PDBsum; 3FRZ; -.
PDBsum; 3G86; -.
PDBsum; 3GYN; -.
PDBsum; 3H2L; -.
PDBsum; 3H59; -.
PDBsum; 3H5S; -.
PDBsum; 3H5U; -.
PDBsum; 3H98; -.
PDBsum; 3IGV; -.
PDBsum; 3MF5; -.
PDBsum; 3RVB; -.
PDBsum; 3UA7; -.
PDBsum; 3UDL; -.
PDBsum; 3VQS; -.
PDBsum; 4A92; -.
PDBsum; 4B6E; -.
PDBsum; 4B6F; -.
PDBsum; 4B71; -.
PDBsum; 4B73; -.
PDBsum; 4B74; -.
PDBsum; 4B75; -.
PDBsum; 4B76; -.
PDBsum; 4DGV; -.
PDBsum; 4DGY; -.
PDBsum; 4EO6; -.
PDBsum; 4EO8; -.
PDBsum; 4IH5; -.
PDBsum; 4IH6; -.
PDBsum; 4IH7; -.
PDBsum; 4K8B; -.
PDBsum; 4KAI; -.
PDBsum; 4KB7; -.
PDBsum; 4KBI; -.
PDBsum; 4KE5; -.
PDBsum; 4MIA; -.
PDBsum; 4MIB; -.
PDBsum; 4MK7; -.
PDBsum; 4MK8; -.
PDBsum; 4MK9; -.
PDBsum; 4MKA; -.
PDBsum; 4MKB; -.
PDBsum; 4TN2; -.
PDBsum; 4WXP; -.
PDBsum; 5FPS; -.
PDBsum; 5FPT; -.
PDBsum; 5FPY; -.
PDBsum; 5KZP; -.
PDBsum; 5W2E; -.
PDBsum; 6MVP; -.
PDBsum; 8OHM; -.
SMR; P26663; -.
IntAct; P26663; 6.
MINT; P26663; -.
BindingDB; P26663; -.
ChEMBL; CHEMBL6040; -.
DrugBank; DB08706; (2S)-({(5Z)-5-[(5-Ethyl-2-furyl)methylene]-4-oxo-4,5-dihydro-1,3-thiazol-2-yl}amino)(4-fluorophenyl)acetic acid.
DrugBank; DB03605; (2s)-2-[(2,4-Dichloro-Benzoyl)-(3-Trifluoromethyl-Benzyl)-Amino]-3-Phenyl-Propionic Acid.
DrugBank; DB02331; (2s)-2-[(5-Benzofuran-2-Yl-Thiophen-2-Ylmethyl)-(2,4-Dichloro-Benzoyl)-Amino]-3-Phenyl-Propionic Acid.
DrugBank; DB07199; (2S,4S,5R)-1-(4-TERT-BUTYLBENZOYL)-2-ISOBUTYL-5-(1,3-THIAZOL-2-YL)PYRROLIDINE-2,4-DICARBOXYLIC ACID.
DrugBank; DB07200; (2S,4S,5R)-2-ISOBUTYL-5-(2-THIENYL)-1-[4-(TRIFLUOROMETHYL)BENZOYL]PYRROLIDINE-2,4-DICARBOXYLIC ACID.
DrugBank; DB07414; (5S)-1-benzyl-3-(1,1-dioxido-1,2-benzisothiazol-3-yl)-4-hydroxy-5-(1-methylethyl)-1,5-dihydro-2H-pyrrol-2-one.
DrugBank; DB08710; (5Z)-5-[(5-ethylfuran-2-yl)methylidene]-2-[[(S)-(4-fluorophenyl)-(2H-tetrazol-5-yl)methyl]amino]-1,3-thiazol-4-one.
DrugBank; DB08390; (6S)-6-CYCLOPENTYL-6-[2-(3-FLUORO-4-ISOPROPOXYPHENYL)ETHYL]-4-HYDROXY-5,6-DIHYDRO-2H-PYRAN-2-ONE.
DrugBank; DB08278; 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone.
DrugBank; DB08701; 2-(3-BROMOPHENYL)-6-[(2-HYDROXYETHYL)AMINO]-1H-BENZO[DE]ISOQUINOLINE-1,3(2H)-DIONE.
DrugBank; DB04298; 3-(4-Amino-2-Tert-Butyl-5-Methyl-Phenylsulfanyl)-6-Cyclopentyl-4-Hydroxy-6-[2-(4-Hydroxy-Phenyl)-Ethyl]-5,6-Dihydro-Pyran-2-One.
DrugBank; DB07570; 3-CYCLOHEXYL-1-(2-MORPHOLIN-4-YL-2-OXOETHYL)-2-PHENYL-1H-INDOLE-6-CARBOXYLIC ACID.
DrugBank; DB08279; 3-{ISOPROPYL[(TRANS-4-METHYLCYCLOHEXYL)CARBONYL]AMINO}-5-PHENYLTHIOPHENE-2-CARBOXYLIC ACID.
DrugBank; DB08581; 4-[(4-bromo-2-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]carbonyl}phenyl)amino]-4-oxobutanoic acid.
DrugBank; DB08578; 4-[(5-bromopyridin-2-yl)amino]-4-oxobutanoic acid.
DrugBank; DB08580; 4-bromo-2-{[(2R)-2-(2-chlorobenzyl)pyrrolidin-1-yl]carbonyl}aniline.
DrugBank; DB08579; 4-bromo-2-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]carbonyl}aniline.
DrugBank; DB08481; 4-Methyl-N-[5-(5-methyl-furan-2-ylmethylene)-4-oxo-thiazolidin-2-ylidene]-benzenesulfonamide.
DrugBank; DB06974; 5-hydroxy-4-(7-methoxy-1,1-dioxido-2H-1,2,4-benzothiadiazin-3-yl)-2-(3-methylbutyl)-6-phenylpyridazin-3(2H)-one.
DrugBank; DB07169; 5R-(3,4-DICHLOROPHENYLMETHYL)-3-(2-THIOPHENESULFONYLAMINO)-4-OXO-2-THIONOTHIAZOLIDINE.
DrugBank; DB11586; Asunaprevir.
DrugBank; DB04137; Guanosine-5'-Triphosphate.
DrugBank; DB08582; N-(4-bromo-2-{[(3R,5S)-3,5-dimethylpiperidin-1-yl]carbonyl}phenyl)-4-morpholin-4-yl-4-oxobutanamide.
DrugBank; DB08031; N-[(13-CYCLOHEXYL-6,7-DIHYDROINDOLO[1,2-D][1,4]BENZOXAZEPIN-10-YL)CARBONYL]-2-METHYL-L-ALANINE.
DrugBank; DB07062; N-{3-[4-Hydroxy-1-(3-methylbutyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxido-2H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide.
DrugBank; DB07238; Nesbuvir.
DrugBank; DB04005; Uridine 5'-triphosphate.
DrugCentral; P26663; -.
iPTMnet; P26663; -.
PRIDE; P26663; -.
ABCD; P26663; 4 sequenced antibodies.
euHCVdb; M58335; -.
BRENDA; 2.7.7.48; 2642.
BRENDA; 3.4.21.98; 2642.
BRENDA; 3.6.4.13; 2642.
EvolutionaryTrace; P26663; -.
Proteomes; UP000007413; Genome.
GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
GO; GO:0030430; C:host cell cytoplasm; IDA:AgBase.
GO; GO:0044164; C:host cell cytosol; IMP:AgBase.
GO; GO:0044167; C:host cell endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
GO; GO:0044186; C:host cell lipid droplet; IEA:UniProtKB-SubCell.
GO; GO:0044191; C:host cell mitochondrial membrane; IEA:UniProtKB-SubCell.
GO; GO:0042025; C:host cell nucleus; IMP:AgBase.
GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
GO; GO:0044385; C:integral to membrane of host cell; IEA:UniProtKB-KW.
GO; GO:0019031; C:viral envelope; IEA:UniProtKB-KW.
GO; GO:0019013; C:viral nucleocapsid; IEA:UniProtKB-KW.
GO; GO:0055036; C:virion membrane; IEA:UniProtKB-SubCell.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
GO; GO:0042802; F:identical protein binding; IPI:IntAct.
GO; GO:0005216; F:ion channel activity; IEA:UniProtKB-KW.
GO; GO:0002020; F:protease binding; IPI:AgBase.
GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
GO; GO:0003724; F:RNA helicase activity; IEA:UniProtKB-EC.
GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IEA:UniProtKB-KW.
GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro.
GO; GO:0008236; F:serine-type peptidase activity; IDA:AgBase.
GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
GO; GO:0075512; P:clathrin-dependent endocytosis of virus by host cell; IEA:UniProtKB-KW.
GO; GO:0039654; P:fusion of virus membrane with host endosome membrane; IEA:UniProtKB-KW.
GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW.
GO; GO:0039645; P:modulation by virus of host G1/S transition checkpoint; IEA:UniProtKB-KW.
GO; GO:0039707; P:pore formation by virus in membrane of host cell; IEA:UniProtKB-KW.
GO; GO:0051259; P:protein complex oligomerization; IEA:UniProtKB-KW.
GO; GO:0039545; P:suppression by virus of host MAVS activity; IEA:UniProtKB-KW.
GO; GO:0039563; P:suppression by virus of host STAT1 activity; IEA:UniProtKB-KW.
GO; GO:0039547; P:suppression by virus of host TRAF activity; IEA:UniProtKB-KW.
GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
GO; GO:0019087; P:transformation of host cell by virus; IEA:InterPro.
GO; GO:0039694; P:viral RNA genome replication; IEA:InterPro.
GO; GO:0019062; P:virion attachment to host cell; IEA:UniProtKB-KW.
Gene3D; 1.20.1280.150; -; 1.
Gene3D; 2.20.25.210; -; 1.
Gene3D; 2.20.25.220; -; 1.
Gene3D; 2.30.30.710; -; 1.
Gene3D; 2.40.10.10; -; 1.
Gene3D; 3.30.70.270; -; 1.
InterPro; IPR011492; DEAD_Flavivir.
InterPro; IPR043502; DNA/RNA_pol_sf.
InterPro; IPR002521; HCV_core_C.
InterPro; IPR002522; HCV_core_N.
InterPro; IPR002519; HCV_env.
InterPro; IPR002531; HCV_NS1.
InterPro; IPR002518; HCV_NS2.
InterPro; IPR042205; HCV_NS2_C.
InterPro; IPR042209; HCV_NS2_N.
InterPro; IPR000745; HCV_NS4a.
InterPro; IPR001490; HCV_NS4b.
InterPro; IPR002868; HCV_NS5a.
InterPro; IPR013193; HCV_NS5a_1B_dom.
InterPro; IPR038568; HCV_NS5A_1B_sf.
InterPro; IPR024350; HCV_NS5a_C.
InterPro; IPR014001; Helicase_ATP-bd.
InterPro; IPR001650; Helicase_C.
InterPro; IPR013192; NS5A_1a.
InterPro; IPR038170; NS5A_1a_sf.
InterPro; IPR027417; P-loop_NTPase.
InterPro; IPR009003; Peptidase_S1_PA.
InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
InterPro; IPR004109; Peptidase_S29_NS3.
InterPro; IPR043128; Rev_trsase/Diguanyl_cyclase.
InterPro; IPR007094; RNA-dir_pol_PSvirus.
InterPro; IPR002166; RNA_pol_HCV.
Pfam; PF07652; Flavi_DEAD; 1.
Pfam; PF01543; HCV_capsid; 1.
Pfam; PF01542; HCV_core; 1.
Pfam; PF01539; HCV_env; 1.
Pfam; PF01560; HCV_NS1; 1.
Pfam; PF01538; HCV_NS2; 1.
Pfam; PF01006; HCV_NS4a; 1.
Pfam; PF01001; HCV_NS4b; 1.
Pfam; PF01506; HCV_NS5a; 1.
Pfam; PF08300; HCV_NS5a_1a; 1.
Pfam; PF08301; HCV_NS5a_1b; 1.
Pfam; PF12941; HCV_NS5a_C; 1.
Pfam; PF02907; Peptidase_S29; 1.
Pfam; PF00998; RdRP_3; 1.
SMART; SM00487; DEXDc; 1.
SUPFAM; SSF50494; SSF50494; 1.
SUPFAM; SSF52540; SSF52540; 2.
SUPFAM; SSF56672; SSF56672; 1.
PROSITE; PS51693; HCV_NS2_PRO; 1.
PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
PROSITE; PS51194; HELICASE_CTER; 1.
PROSITE; PS51822; HV_PV_NS3_PRO; 1.
PROSITE; PS50507; RDRP_SSRNA_POS; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Activation of host autophagy by virus;
Apoptosis; ATP-binding; Capsid protein;
Clathrin-mediated endocytosis of virus by host; Direct protein sequencing;
Disulfide bond; Fusion of virus membrane with host endosomal membrane;
Fusion of virus membrane with host membrane;
G1/S host cell cycle checkpoint dysregulation by virus; Glycoprotein;
Helicase; Host cell membrane; Host cytoplasm; Host endoplasmic reticulum;
Host lipid droplet; Host membrane; Host mitochondrion; Host nucleus;
Host-virus interaction; Hydrolase;
Inhibition of host innate immune response by virus;
Inhibition of host interferon signaling pathway by virus;
Inhibition of host MAVS by virus; Inhibition of host RLR pathway by virus;
Inhibition of host STAT1 by virus; Inhibition of host TRAFs by virus;
Interferon antiviral system evasion; Ion channel; Ion transport;
Lipoprotein; Membrane; Metal-binding;
Modulation of host cell cycle by virus; Multifunctional enzyme;
Nucleotide-binding; Nucleotidyltransferase; Oncogene; Palmitate;
Phosphoprotein; Protease; Ribonucleoprotein; RNA-binding;
RNA-directed RNA polymerase; Secreted; Serine protease; SH3-binding;
Thiol protease; Transcription; Transcription regulation; Transferase;
Transmembrane; Transmembrane helix; Transport; Ubl conjugation;
Viral attachment to host cell; Viral envelope protein; Viral immunoevasion;
Viral ion channel; Viral nucleoprotein;
Viral penetration into host cytoplasm; Viral RNA replication; Virion;
Virus endocytosis by host; Virus entry into host cell; Zinc.
INIT_MET 1
/note="Removed; by host"
/evidence="ECO:0000250"
CHAIN 2..191
/note="Core protein p21"
/evidence="ECO:0000255"
/id="PRO_0000037529"
CHAIN 2..177
/note="Core protein p19"
/evidence="ECO:0000250"
/id="PRO_0000037530"
PROPEP 178..191
/note="ER anchor for the core protein, removed in mature
form by host signal peptidase"
/evidence="ECO:0000250"
/id="PRO_0000037531"
CHAIN 192..383
/note="Envelope glycoprotein E1"
/evidence="ECO:0000255"
/id="PRO_0000037532"
CHAIN 384..746
/note="Envelope glycoprotein E2"
/evidence="ECO:0000255"
/id="PRO_0000037533"
CHAIN 747..809
/note="p7"
/evidence="ECO:0000250"
/id="PRO_0000037534"
CHAIN 810..1026
/note="Protease NS2-3"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
/id="PRO_0000037535"
CHAIN 1027..1657
/note="Serine protease NS3"
/id="PRO_0000037536"
CHAIN 1658..1711
/note="Non-structural protein 4A"
/id="PRO_0000037537"
CHAIN 1712..1972
/note="Non-structural protein 4B"
/id="PRO_0000037538"
CHAIN 1973..2419
/note="Non-structural protein 5A"
/id="PRO_0000037539"
CHAIN 2420..3010
/note="RNA-directed RNA polymerase"
/id="PRO_0000037540"
TOPO_DOM 2..168
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 169..189
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 190..358
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 359..379
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 380..725
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 726..746
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 747..757
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 758..778
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 779..782
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 783..803
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 804..813
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 814..834
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 835..881
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 882..902
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 903..928
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 929..949
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 950..1657
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 1658..1678
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1679..1805
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 1806..1826
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1827..1828
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 1829..1849
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1850
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 1851..1871
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1872..1881
/note="Lumenal"
/evidence="ECO:0000255"
TRANSMEM 1882..1902
/note="Helical"
/evidence="ECO:0000255"
TOPO_DOM 1903..1972
/note="Cytoplasmic"
/evidence="ECO:0000255"
INTRAMEM 1973..2002
/evidence="ECO:0000250"
TOPO_DOM 2003..2989
/note="Cytoplasmic"
/evidence="ECO:0000255"
TRANSMEM 2990..3010
/note="Helical"
/evidence="ECO:0000250"
DOMAIN 903..1026
/note="Peptidase C18"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
DOMAIN 1027..1208
/note="Peptidase S29"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
DOMAIN 1217..1369
/note="Helicase ATP-binding"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
DOMAIN 2633..2751
/note="RdRp catalytic"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
NP_BIND 1230..1237
/note="ATP"
/evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
REGION 2..59
/note="Interaction with DDX3X"
/evidence="ECO:0000250"
REGION 2..23
/note="Interaction with STAT1"
/evidence="ECO:0000250"
REGION 122..173
/note="Interaction with APOA2"
/evidence="ECO:0000250"
REGION 148..236
/note="Interaction with FKBP8"
REGION 150..159
/note="Mitochondrial targeting signal"
/evidence="ECO:0000250"
REGION 164..167
/note="Important for lipid droplets localization"
/evidence="ECO:0000250"
REGION 265..296
/note="Fusion peptide"
/evidence="ECO:0000255"
REGION 385..411
/note="HVR1"
REGION 475..481
/note="HVR2"
REGION 482..494
/note="CD81-binding 1"
/evidence="ECO:0000255"
REGION 522..553
/note="CD81-binding 2"
/evidence="ECO:0000255"
REGION 660..671
/note="PKR/eIF2-alpha phosphorylation homology domain
(PePHD)"
REGION 1679..1690
/note="NS3-binding (by NS4A)"
/evidence="ECO:0000255"
REGION 2120..2332
/note="Transcriptional activation"
/evidence="ECO:0000255"
REGION 2120..2208
/note="FKBP8-binding"
/evidence="ECO:0000255"
REGION 2200..2250
/note="Basal phosphorylation"
/evidence="ECO:0000250"
REGION 2210..2275
/note="PKR-binding"
/evidence="ECO:0000255"
REGION 2210..2249
/note="ISDR"
REGION 2249..2306
/note="NS4B-binding"
/evidence="ECO:0000255"
REGION 2351..2419
/note="Basal phosphorylation"
/evidence="ECO:0000250"
REGION 2354..2377
/note="V3"
MOTIF 5..13
/note="Nuclear localization signal"
/evidence="ECO:0000255"
MOTIF 38..43
/note="Nuclear localization signal"
/evidence="ECO:0000255"
MOTIF 58..64
/note="Nuclear localization signal"
/evidence="ECO:0000255"
MOTIF 66..71
/note="Nuclear localization signal"
/evidence="ECO:0000255"
MOTIF 1316..1319
/note="DECH box"
MOTIF 2322..2325
/note="SH3-binding"
/evidence="ECO:0000255"
MOTIF 2327..2335
/note="Nuclear localization signal"
/evidence="ECO:0000255"
COMPBIAS 796..803
/note="Poly-Leu"
COMPBIAS 1432..1435
/note="Poly-Val"
COMPBIAS 2282..2327
/note="Pro-rich"
COMPBIAS 2995..2998
/note="Poly-Leu"
ACT_SITE 952
/note="For protease NS2-3 activity; shared with dimeric
partner"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
ACT_SITE 972
/note="For protease NS2-3 activity; shared with dimeric
partner"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
ACT_SITE 993
/note="For protease NS2-3 activity; shared with dimeric
partner"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
ACT_SITE 1083
/note="Charge relay system; for serine protease NS3
activity"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
ACT_SITE 1107
/note="Charge relay system; for serine protease NS3
activity"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
ACT_SITE 1165
/note="Charge relay system; for serine protease NS3
activity"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1123
/note="Zinc"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1125
/note="Zinc"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1171
/note="Zinc"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 1175
/note="Zinc"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01166"
METAL 2011
/note="Zinc"
/evidence="ECO:0000250"
METAL 2029
/note="Zinc"
/evidence="ECO:0000250"
METAL 2031
/note="Zinc"
/evidence="ECO:0000250"
METAL 2052
/note="Zinc"
/evidence="ECO:0000250"
SITE 177..178
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000250"
SITE 191..192
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000255"
SITE 383..384
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000255"
SITE 746..747
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000250"
SITE 809..810
/note="Cleavage; by host signal peptidase"
/evidence="ECO:0000250"
SITE 1026..1027
/note="Cleavage; by protease NS2-3"
/evidence="ECO:0000255|PROSITE-ProRule:PRU01030"
SITE 1657..1658
/note="Cleavage; by serine protease NS3"
/evidence="ECO:0000255"
SITE 1711..1712
/note="Cleavage; by serine protease NS3"
/evidence="ECO:0000255"
SITE 1972..1973
/note="Cleavage; by serine protease NS3"
/evidence="ECO:0000255"
SITE 2419..2420
/note="Cleavage; by serine protease NS3"
/evidence="ECO:0000255"
MOD_RES 2
/note="N-acetylserine; by host"
/evidence="ECO:0000250"
MOD_RES 53
/note="Phosphoserine; by host"
/evidence="ECO:0000250"
MOD_RES 99
/note="Phosphoserine; by host"
/evidence="ECO:0000250"
MOD_RES 116
/note="Phosphoserine; by host PKA"
/evidence="ECO:0000250"
MOD_RES 2194
/note="Phosphoserine; by host; in p56"
/evidence="ECO:0000269|PubMed:11118372"
MOD_RES 2197
/note="Phosphoserine; by host; in p58"
/evidence="ECO:0000250"
MOD_RES 2201
/note="Phosphoserine; by host; in p58"
/evidence="ECO:0000250"
MOD_RES 2204
/note="Phosphoserine; by host; in p58"
/evidence="ECO:0000250"
LIPID 1968
/note="S-palmitoyl cysteine; by host"
/evidence="ECO:0000250"
LIPID 1972
/note="S-palmitoyl cysteine; by host"
/evidence="ECO:0000250"
CARBOHYD 196
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 209
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 234
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 250
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 305
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 417
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 423
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 430
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 448
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 532
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 540
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 556
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 576
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 623
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
CARBOHYD 645
/note="N-linked (GlcNAc...) asparagine; by host"
/evidence="ECO:0000255"
DISULFID 2114..2162
/evidence="ECO:0000250"
MUTAGEN 2194
/note="S->A: Loss of phosphorylation."
/evidence="ECO:0000269|PubMed:11118372"
MUTAGEN 2322
/note="P->A: Complete loss of binding to GRB2."
/evidence="ECO:0000269|PubMed:10318918"
MUTAGEN 2323
/note="P->A: Complete loss of binding to GRB2."
/evidence="ECO:0000269|PubMed:10318918"
MUTAGEN 2326
/note="P->A: Complete loss of binding to GRB2."
/evidence="ECO:0000269|PubMed:10318918"
STRAND 413..416
/evidence="ECO:0000244|PDB:4DGY"
STRAND 419..422
/evidence="ECO:0000244|PDB:4DGY"
STRAND 1017..1023
/evidence="ECO:0000244|PDB:4B76"
STRAND 1031..1035
/evidence="ECO:0000244|PDB:4B76"
HELIX 1039..1048
/evidence="ECO:0000244|PDB:4B76"
STRAND 1057..1063
/evidence="ECO:0000244|PDB:4B76"
STRAND 1068..1074
/evidence="ECO:0000244|PDB:4B76"
STRAND 1077..1080
/evidence="ECO:0000244|PDB:4B76"
HELIX 1082..1085
/evidence="ECO:0000244|PDB:4B76"
STRAND 1090..1092
/evidence="ECO:0000244|PDB:1JXP"
STRAND 1095..1097
/evidence="ECO:0000244|PDB:1JXP"
STRAND 1100..1103
/evidence="ECO:0000244|PDB:4B76"
TURN 1104..1107
/evidence="ECO:0000244|PDB:4B76"
STRAND 1108..1112
/evidence="ECO:0000244|PDB:4B76"
STRAND 1128..1133
/evidence="ECO:0000244|PDB:4B76"
STRAND 1135..1137
/evidence="ECO:0000244|PDB:1BT7"
STRAND 1139..1144
/evidence="ECO:0000244|PDB:4B76"
STRAND 1146..1157
/evidence="ECO:0000244|PDB:4B76"
HELIX 1158..1161
/evidence="ECO:0000244|PDB:4B76"
STRAND 1168..1170
/evidence="ECO:0000244|PDB:4B76"
TURN 1172..1174
/evidence="ECO:0000244|PDB:1JXP"
STRAND 1176..1186
/evidence="ECO:0000244|PDB:4B76"
STRAND 1189..1197
/evidence="ECO:0000244|PDB:4B76"
HELIX 1198..1206
/evidence="ECO:0000244|PDB:4B76"
STRAND 1224..1229
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1232..1235
/evidence="ECO:0000244|PDB:1CU1"
TURN 1236..1238
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1239..1246
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1251..1256
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1258..1272
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1277..1279
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1290..1295
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1296..1301
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1307..1309
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1311..1315
/evidence="ECO:0000244|PDB:4WXP"
TURN 1316..1319
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1323..1335
/evidence="ECO:0000244|PDB:4WXP"
TURN 1336..1340
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1342..1350
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1362..1366
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1371..1375
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1378..1380
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1382..1384
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1386..1393
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1397..1409
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1414..1417
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1419..1421
/evidence="ECO:0000244|PDB:8OHM"
HELIX 1423..1425
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1428..1430
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1432..1436
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1438..1441
/evidence="ECO:0000244|PDB:4WXP"
TURN 1442..1444
/evidence="ECO:0000244|PDB:8OHM"
STRAND 1448..1453
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1456..1463
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1467..1469
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1471..1478
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1481..1488
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1493..1495
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1497..1503
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1509..1511
/evidence="ECO:0000244|PDB:4B76"
HELIX 1514..1526
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1532..1544
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1555..1563
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1570..1579
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1584..1596
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1606..1611
/evidence="ECO:0000244|PDB:4WXP"
TURN 1612..1614
/evidence="ECO:0000244|PDB:4WXP"
HELIX 1615..1617
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1625..1629
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1635..1637
/evidence="ECO:0000244|PDB:8OHM"
HELIX 1640..1650
/evidence="ECO:0000244|PDB:4WXP"
TURN 1653..1655
/evidence="ECO:0000244|PDB:4WXP"
STRAND 1680..1688
/evidence="ECO:0000244|PDB:1JXP"
STRAND 1690..1693
/evidence="ECO:0000244|PDB:1CU1"
STRAND 2421..2425
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2446..2449
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2453..2455
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2456..2458
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2461..2463
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2464..2471
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2481..2494
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2504..2509
/evidence="ECO:0000244|PDB:2GIQ"
TURN 2519..2521
/evidence="ECO:0000244|PDB:2WRM"
HELIX 2524..2528
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2532..2547
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2549..2551
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2555..2559
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2563..2565
/evidence="ECO:0000244|PDB:2GIQ"
TURN 2568..2571
/evidence="ECO:0000244|PDB:1GX5"
STRAND 2578..2581
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2584..2606
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2607..2609
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2611..2613
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2616..2629
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2630..2638
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2643..2646
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2649..2659
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2666..2678
/evidence="ECO:0000244|PDB:2GIQ"
TURN 2679..2681
/evidence="ECO:0000244|PDB:1GX6"
STRAND 2683..2686
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2688..2690
/evidence="ECO:0000244|PDB:1CSJ"
STRAND 2692..2696
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2701..2703
/evidence="ECO:0000244|PDB:2HWI"
HELIX 2706..2724
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2728..2735
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2738..2744
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2748..2764
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2769..2771
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2776..2778
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2779..2781
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2787..2793
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2795..2797
/evidence="ECO:0000244|PDB:3CVK"
STRAND 2799..2804
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2808..2819
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2826..2833
/evidence="ECO:0000244|PDB:2GIQ"
TURN 2834..2836
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2838..2842
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2844..2854
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2858..2860
/evidence="ECO:0000244|PDB:3BSA"
STRAND 2862..2866
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2869..2873
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2875..2877
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2878..2886
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2888..2891
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2898..2911
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2916..2933
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2935..2944
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2946..2948
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2949..2951
/evidence="ECO:0000244|PDB:2GIQ"
HELIX 2959..2962
/evidence="ECO:0000244|PDB:2GIQ"
TURN 2967..2970
/evidence="ECO:0000244|PDB:2GIQ"
STRAND 2976..2978
/evidence="ECO:0000244|PDB:4KE5"
STRAND 2980..2982
/evidence="ECO:0000244|PDB:4EO6"
SEQUENCE 3010 AA; 327194 MW; F8422D5ECCFDFD9C CRC64;
MSTNPKPQRK TKRNTNRRPQ DVKFPGGGQI VGGVYLLPRR GPRLGVRAPR KTSERSQPRG
RRQPIPKARR PEGRTWAQPG YPWPLYGNEG LGWAGWLLSP RGSRPSWGPT DPRRRSRNLG
KVIDTLTCGF ADLMGYIPLV GAPLGGAARA LAHGVRVLED GVNYATGNLP GCSFSIFLLA
LLSCLTTPAS AYEVHNVSGI YHVTNDCSNA SIVYEAADLI MHTPGCVPCV REGNSSRCWV
ALTPTLAARN VTIPTTTIRR HVDLLVGAAA FCSAMYVGDL CGSVFLVSQL FTFSPRRHVT
LQDCNCSIYP GHVSGHRMAW DMMMNWSPTT ALVVSQLLRI PQAVVDMVAG AHWGVLAGLA
YYSMAGNWAK VLIVMLLFAG VDGDTHVTGG AQAKTTNRLV SMFASGPSQK IQLINTNGSW
HINRTALNCN DSLQTGFLAA LFYTHSFNSS GCPERMAQCR TIDKFDQGWG PITYAESSRS
DQRPYCWHYP PPQCTIVPAS EVCGPVYCFT PSPVVVGTTD RFGVPTYRWG ENETDVLLLN
NTRPPQGNWF GCTWMNSTGF TKTCGGPPCN IGGVGNNTLT CPTDCFRKHP EATYTKCGSG
PWLTPRCMVD YPYRLWHYPC TVNFTIFKVR MYVGGVEHRL NAACNWTRGE RCDLEDRDRP
ELSPLLLSTT EWQVLPCSFT TLPALSTGLI HLHQNIVDVQ YLYGIGSAVV SFAIKWEYVL
LLFLLLADAR VCACLWMMLL IAQAEAALEN LVVLNSASVA GAHGILSFLV FFCAAWYIKG
RLVPGATYAL YGVWPLLLLL LALPPRAYAM DREMAASCGG AVFVGLVLLT LSPYYKVFLA
RLIWWLQYFT TRAEADLHVW IPPLNARGGR DAIILLMCAV HPELIFDITK LLIAILGPLM
VLQAGITRVP YFVRAQGLIH ACMLVRKVAG GHYVQMAFMK LGALTGTYIY NHLTPLRDWP
RAGLRDLAVA VEPVVFSDME TKIITWGADT AACGDIILGL PVSARRGKEI LLGPADSLEG
RGLRLLAPIT AYSQQTRGLL GCIITSLTGR DKNQVEGEVQ VVSTATQSFL ATCVNGVCWT
VYHGAGSKTL AAPKGPITQM YTNVDQDLVG WPKPPGARSL TPCTCGSSDL YLVTRHADVI
PVRRRGDSRG SLLSPRPVSY LKGSSGGPLL CPFGHAVGIF RAAVCTRGVA KAVDFVPVES
METTMRSPVF TDNSSPPAVP QSFQVAHLHA PTGSGKSTKV PAAYAAQGYK VLVLNPSVAA
TLGFGAYMSK AHGIDPNIRT GVRTITTGAP VTYSTYGKFL ADGGCSGGAY DIIICDECHS
TDSTTILGIG TVLDQAETAG ARLVVLATAT PPGSVTVPHP NIEEVALSNT GEIPFYGKAI
PIEAIRGGRH LIFCHSKKKC DELAAKLSGL GINAVAYYRG LDVSVIPTIG DVVVVATDAL
MTGYTGDFDS VIDCNTCVTQ TVDFSLDPTF TIETTTVPQD AVSRSQRRGR TGRGRRGIYR
FVTPGERPSG MFDSSVLCEC YDAGCAWYEL TPAETSVRLR AYLNTPGLPV CQDHLEFWES
VFTGLTHIDA HFLSQTKQAG DNFPYLVAYQ ATVCARAQAP PPSWDQMWKC LIRLKPTLHG
PTPLLYRLGA VQNEVTLTHP ITKYIMACMS ADLEVVTSTW VLVGGVLAAL AAYCLTTGSV
VIVGRIILSG RPAIVPDREL LYQEFDEMEE CASHLPYIEQ GMQLAEQFKQ KALGLLQTAT
KQAEAAAPVV ESKWRALETF WAKHMWNFIS GIQYLAGLST LPGNPAIASL MAFTASITSP
LTTQSTLLFN ILGGWVAAQL APPSAASAFV GAGIAGAAVG SIGLGKVLVD ILAGYGAGVA
GALVAFKVMS GEMPSTEDLV NLLPAILSPG ALVVGVVCAA ILRRHVGPGE GAVQWMNRLI
AFASRGNHVS PTHYVPESDA AARVTQILSS LTITQLLKRL HQWINEDCST PCSGSWLRDV
WDWICTVLTD FKTWLQSKLL PQLPGVPFFS CQRGYKGVWR GDGIMQTTCP CGAQITGHVK
NGSMRIVGPK TCSNTWHGTF PINAYTTGPC TPSPAPNYSR ALWRVAAEEY VEVTRVGDFH
YVTGMTTDNV KCPCQVPAPE FFSEVDGVRL HRYAPACRPL LREEVTFQVG LNQYLVGSQL
PCEPEPDVAV LTSMLTDPSH ITAETAKRRL ARGSPPSLAS SSASQLSAPS LKATCTTHHV
SPDADLIEAN LLWRQEMGGN ITRVESENKV VVLDSFDPLR AEEDEREVSV PAEILRKSKK
FPAAMPIWAR PDYNPPLLES WKDPDYVPPV VHGCPLPPIK APPIPPPRRK RTVVLTESSV
SSALAELATK TFGSSESSAV DSGTATALPD QASDDGDKGS DVESYSSMPP LEGEPGDPDL
SDGSWSTVSE EASEDVVCCS MSYTWTGALI TPCAAEESKL PINALSNSLL RHHNMVYATT
SRSAGLRQKK VTFDRLQVLD DHYRDVLKEM KAKASTVKAK LLSVEEACKL TPPHSAKSKF
GYGAKDVRNL SSKAVNHIHS VWKDLLEDTV TPIDTTIMAK NEVFCVQPEK GGRKPARLIV
FPDLGVRVCE KMALYDVVST LPQVVMGSSY GFQYSPGQRV EFLVNTWKSK KNPMGFSYDT
RCFDSTVTEN DIRVEESIYQ CCDLAPEARQ AIKSLTERLY IGGPLTNSKG QNCGYRRCRA
SGVLTTSCGN TLTCYLKASA ACRAAKLQDC TMLVNGDDLV VICESAGTQE DAASLRVFTE
AMTRYSAPPG DPPQPEYDLE LITSCSSNVS VAHDASGKRV YYLTRDPTTP LARAAWETAR
HTPVNSWLGN IIMYAPTLWA RMILMTHFFS ILLAQEQLEK ALDCQIYGAC YSIEPLDLPQ
IIERLHGLSA FSLHSYSPGE INRVASCLRK LGVPPLRVWR HRARSVRARL LSQGGRAATC
GKYLFNWAVK TKLKLTPIPA ASRLDLSGWF VAGYSGGDIY HSLSRARPRW FMLCLLLLSV
GVGIYLLPNR


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