4j08 - Revision history

OCA at 15:34, 20 September 2023

2023-09-20T15:34:38Z

←Older revision		Revision as of 15:34, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4j08]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_isolate_HC-J4 Hepatitis C virus isolate HC-J4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J08 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4j08]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_isolate_HC-J4 Hepatitis C virus isolate HC-J4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J08 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1JH:2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC+ACID'>1JH</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.1Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1JH:2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC+ACID'>1JH</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4j08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j08 OCA], [https://pdbe.org/4j08 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j08 RCSB], [https://www.ebi.ac.uk/pdbsum/4j08 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j08 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4j08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j08 OCA], [https://pdbe.org/4j08 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j08 RCSB], [https://www.ebi.ac.uk/pdbsum/4j08 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j08 ProSAT]</span></td></tr>
	</table>		</table>

OCA at 21:22, 16 November 2022

2022-11-16T21:22:10Z

←Older revision		Revision as of 21:22, 16 November 2022
Line 1:		Line 1:

	==Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID==		==Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID==
-	<StructureSection load='4j08' size='340' side='right' caption='[[4j08]], [[Resolution\|resolution]] 2.10Å' scene=''>	+	<StructureSection load='4j08' size='340' side='right'caption='[[4j08]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4j08]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Hcv Hcv~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4J08 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4j08]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_isolate_HC-J4 Hepatitis C virus isolate HC-J4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J08 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1JH:2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC+ACID'>1JH</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1JH:2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC+ACID'>1JH</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3mwv\|3mwv]], [[4iz0\|4iz0]], [[4j04\|4j04]], [[4j06\|4j06]], [[4j02\|4j02]], [[4j0a\|4j0a]]</td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4j08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j08 OCA], [https://pdbe.org/4j08 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j08 RCSB], [https://www.ebi.ac.uk/pdbsum/4j08 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j08 ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=420174 HCV])~~</td></tr>	+
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4j08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j08 OCA], [~~http~~://pdbe.org/4j08 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4j08 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4j08 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4j08 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] 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). 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). 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). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). 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). 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). 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). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).	+	[https://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4] 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). 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). 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). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). 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). 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). 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). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 20:

	==See Also==		==See Also==
-	*[[RNA polymerase\|RNA polymerase]]	+	*[[RNA polymerase 3D structures\|RNA polymerase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Hcv]]~~	+	[[Category: Hepatitis C virus isolate HC-J4]]
-	~~[[Category: Coulombe,R]]~~	+	[[Category: Large Structures]]
-	~~[[Category: Rna~~-~~directed rna polymerase~~]]	+	[[Category: Coulombe R]]
-	[[Category: ~~Transferase~~]]	+
-	[[Category: ~~Transferase-transferase inhibitor complex~~]]	+

OCA at 18:50, 4 August 2016

2016-08-04T18:50:41Z

←Older revision		Revision as of 18:50, 4 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID==		==Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID==
	<StructureSection load='4j08' size='340' side='right' caption='[[4j08]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='4j08' size='340' side='right' caption='[[4j08]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4j08]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Hepatitis_c_virus_isolate_hc-j4 Hepatitis c virus isolate hc-j4~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J08 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4j08]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hcv Hcv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J08 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1JH:2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC+ACID'>1JH</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1JH:2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC+ACID'>1JH</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3mwv\|3mwv]], [[4iz0\|4iz0]], [[4j04\|4j04]], [[4j06\|4j06]], [[4j02\|4j02]], [[4j0a\|4j0a]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3mwv\|3mwv]], [[4iz0\|4iz0]], [[4j04\|4j04]], [[4j06\|4j06]], [[4j02\|4j02]], [[4j0a\|4j0a]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=420174 ~~Hepatitis C virus isolate HC-J4~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=420174 HCV])</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4j08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j08 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4j08 RCSB], [http://www.ebi.ac.uk/pdbsum/4j08 PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4j08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j08 OCA], [http://pdbe.org/4j08 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4j08 RCSB], [http://www.ebi.ac.uk/pdbsum/4j08 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4j08 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4j08" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Hepatitis c virus isolate hc-j4~~]]	+	[[Category: Hcv]]
	[[Category: Coulombe,R]]		[[Category: Coulombe,R]]
	[[Category: Rna-directed rna polymerase]]		[[Category: Rna-directed rna polymerase]]
	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 18:23, 24 December 2014

2014-12-24T18:23:45Z

←Older revision		Revision as of 18:23, 24 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4j08\| PDB=4j08 \| SCENE= }}~~	+	==Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID==
-	===Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID===	+	<StructureSection load='4j08' size='340' side='right' caption='[[4j08]], [[Resolution\|resolution]] 2.10Å' scene=''>
-	{~~{ABSTRACT_PUBMED_23545108}~~}	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4j08]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_isolate_hc-j4 Hepatitis c virus isolate hc-j4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J08 FirstGlance]. <br>
-	==Function==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1JH:2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC+ACID'>1JH</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3mwv\|3mwv]], [[4iz0\|4iz0]], [[4j04\|4j04]], [[4j06\|4j06]], [[4j02\|4j02]], [[4j0a\|4j0a]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=420174 Hepatitis C virus isolate HC-J4])</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4j08 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j08 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4j08 RCSB], [http://www.ebi.ac.uk/pdbsum/4j08 PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
	[[http://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] 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). 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). 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). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). 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). 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). 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). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).		[[http://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] 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). 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). 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). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). 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). 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). 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). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point.
		+
		+	Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors.,Stammers TA, Coulombe R, Rancourt J, Thavonekham B, Fazal G, Goulet S, Jakalian A, Wernic D, Tsantrizos Y, Poupart MA, Bos M, McKercher G, Thauvette L, Kukolj G, Beaulieu PL Bioorg Med Chem Lett. 2013 May 1;23(9):2585-9. doi: 10.1016/j.bmcl.2013.02.110., Epub 2013 Mar 7. PMID:23545108<ref>PMID:23545108</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

-	==~~About this Structure~~==	+	==See Also==
-	[[~~4j08~~]] ~~is a 2 chain structure with sequence from [http:~~//~~en.wikipedia.org/wiki/Hepatitis_c_virus_isolate_hc-j4 Hepatitis c virus isolate hc-j4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA].~~	+	*[[RNA polymerase\|RNA polymerase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Hepatitis c virus isolate hc-j4]]		[[Category: Hepatitis c virus isolate hc-j4]]
-	[[Category: Coulombe,R.]]	+	[[Category: Coulombe,R]]
	[[Category: Rna-directed rna polymerase]]		[[Category: Rna-directed rna polymerase]]
	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 20:24, 17 April 2013

2013-04-17T20:24:21Z

←Older revision		Revision as of 20:24, 17 April 2013
Line 1:		Line 1:
-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4j08\| PDB=4j08 \| SCENE= }}
		+	===Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID===
		+	{{ABSTRACT_PUBMED_23545108}}

-	The ~~entry 4j08~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	==Function==
		+	[[http://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] 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). 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). 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). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). 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). 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). 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). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).

-	~~Authors~~: Coulombe,R.	+	==About this Structure==
-		+	[[4j08]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_isolate_hc-j4 Hepatitis c virus isolate hc-j4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J08 OCA].
-	~~Description~~: ~~Crystal structure of hcv ns5b polymerase in complex with 2~~-{[~~(4-METHYLPHENYL)SULFONYL~~]~~AMINO}~~-~~5-PHENOXYBENZOIC ACID~~	+	[[Category: Hepatitis c virus isolate hc-j4]]
		+	[[Category: Coulombe,R.]]
		+	[[Category: Rna-directed rna polymerase]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 16:15, 20 March 2013

2013-03-20T16:15:28Z

←Older revision		Revision as of 16:15, 20 March 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4j08 is ON HOLD	+	The entry 4j08 is ON HOLD until Paper Publication

	Authors: Coulombe,R.		Authors: Coulombe,R.

	Description: Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID		Description: Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID

OCA at 14:22, 27 February 2013

2013-02-27T14:22:21Z

←Older revision		Revision as of 14:22, 27 February 2013
Line 5:		Line 5:
	Authors: Coulombe,R.		Authors: Coulombe,R.

-	Description: ~~CRYSTAL STRUCTURE OF HCV NS5B POLYMERASE IN COMPLEX WITH COMPOUND 11B~~	+	Description: Crystal structure of hcv ns5b polymerase in complex with 2-{[(4-METHYLPHENYL)SULFONYL]AMINO}-5-PHENOXYBENZOIC ACID

OCA: Protected "4j08" [edit=sysop:move=sysop]

2013-02-06T12:33:36Z

Protected "4j08" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:33, 6 February 2013

OCA: New page: '''Unreleased structure''' The entry 4j08 is ON HOLD Authors: Coulombe,R. Description: CRYSTAL STRUCTURE OF HCV NS5B POLYMERASE IN COMPLEX WITH COMPOUND 11B

2013-02-06T12:33:35Z

New page: '''Unreleased structure''' The entry 4j08 is ON HOLD Authors: Coulombe,R. Description: CRYSTAL STRUCTURE OF HCV NS5B POLYMERASE IN COMPLEX WITH COMPOUND 11B

New page

'''Unreleased structure'''

The entry 4j08 is ON HOLD

Authors: Coulombe,R.

Description: CRYSTAL STRUCTURE OF HCV NS5B POLYMERASE IN COMPLEX WITH COMPOUND 11B