3qgf - Revision history

OCA at 11:44, 14 March 2024

OCA — Thu, 14 Mar 2024 11:44:49 GMT

←Older revision		Revision as of 11:44, 14 March 2024
Line 3:		Line 3:
	<StructureSection load='3qgf' size='340' side='right'caption='[[3qgf]], [[Resolution\|resolution]] 2.45Å' scene=''>		<StructureSection load='3qgf' size='340' side='right'caption='[[3qgf]], [[Resolution\|resolution]] 2.45Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qgf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Hepatitis_c_virus_subtype_1b~~ Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QGF FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qgf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_subtype_1b Hepatitis C virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QGF FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=23E:(2E)-3-(4-{[(1-{[(13-CYCLOHEXYL-6-OXO-6,7-DIHYDRO-5H-INDOLO[1,2-D][1,4]BENZODIAZEPIN-10-YL)CARBONYL]AMINO}CYCLOPENTYL)CARBONYL]AMINO}PHENYL)PROP-2-ENOIC+ACID'>23E</scene>, <scene name='pdbligand=46F:(2R)-4-(6-CHLOROPYRIDAZIN-3-YL)-N-(4-METHOXYBENZYL)-1-{[4-(TRIFLUOROMETHOXY)PHENYL]SULFONYL}PIPERAZINE-2-CARBOXAMIDE'>46F</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.45Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qgd\|3qgd]], [[3qge\|3qge]], [[3qgg\|3qgg]], [[3qgh\|3qgh]], [[3qgi\|3qgi]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=23E:(2E)-3-(4-{[(1-{[(13-CYCLOHEXYL-6-OXO-6,7-DIHYDRO-5H-INDOLO[1,2-D][1,4]BENZODIAZEPIN-10-YL)CARBONYL]AMINO}CYCLOPENTYL)CARBONYL]AMINO}PHENYL)PROP-2-ENOIC+ACID'>23E</scene>, <scene name='pdbligand=46F:(2R)-4-(6-CHLOROPYRIDAZIN-3-YL)-N-(4-METHOXYBENZYL)-1-{[4-(TRIFLUOROMETHOXY)PHENYL]SULFONYL}PIPERAZINE-2-CARBOXAMIDE'>46F</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS5B ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31647 Hepatitis C virus subtype 1b])</td></tr>	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [https://pdbe.org/3qgf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [https://www.ebi.ac.uk/pdbsum/3qgf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgf 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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [https://pdbe.org/3qgf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [https://www.ebi.ac.uk/pdbsum/3qgf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgf ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/POLG_HCVCO POLG_HCVCO]] 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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 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 the host antiviral protein MAVS (By similarity). NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state.<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref>	+	[https://www.uniprot.org/uniprot/POLG_HCVCO POLG_HCVCO] 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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 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 the host antiviral protein MAVS (By similarity). NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state.<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide inhibitors of the hepatitis C viral polymerase are described herein. These compounds bind to the hepatitis C virus non-structural protein 5B (NS5B), and co-crystal structures of select examples from this series with NS5B are reported. Comparison of co-crystal structures of a potent analog with both NS5B genotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series.	+
-		+
-	Investigation of the mode of binding of a novel series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides to the hepatitis C virus polymerase.,Gentles RG, Sheriff S, Beno BR, Wan C, Kish K, Ding M, Zheng X, Chupak L, Poss MA, Witmer MR, Morin P, Wang YK, Rigat K, Lemm J, Voss S, Liu M, Pelosi L, Roberts SB, Gao M, Kadow JF Bioorg Med Chem Lett. 2011 Apr 15;21(8):2212-5. Epub 2011 Mar 6. PMID:21441029<ref>PMID:21441029</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3qgf" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 28:		Line 17:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Hepatitis c virus subtype 1b]]	+	[[Category: Hepatitis C virus subtype 1b]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: RNA-directed RNA polymerase]]~~	+	[[Category: Sheriff S]]
-	[[Category: Sheriff, S]]	+
-	~~[[Category: Finger]]~~	+
-	~~[[Category: Hcv]]~~	+
-	~~[[Category: Ns5b]]~~	+
-	~~[[Category: Palm]]~~	+
-	~~[[Category: Polymerase]]~~	+
-	~~[[Category: Thumb]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 06:08, 8 June 2022

OCA — Wed, 08 Jun 2022 06:08:00 GMT

←Older revision		Revision as of 06:08, 8 June 2022
Line 1:		Line 1:

	==Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide==		==Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide==
-	<StructureSection load='3qgf' size='340' side='right' caption='[[3qgf]], [[Resolution\|resolution]] 2.45Å' scene=''>	+	<StructureSection load='3qgf' size='340' side='right'caption='[[3qgf]], [[Resolution\|resolution]] 2.45Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3qgf]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3QGF FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3qgf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QGF FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=23E:(2E)-3-(4-{[(1-{[(13-CYCLOHEXYL-6-OXO-6,7-DIHYDRO-5H-INDOLO[1,2-D][1,4]BENZODIAZEPIN-10-YL)CARBONYL]AMINO}CYCLOPENTYL)CARBONYL]AMINO}PHENYL)PROP-2-ENOIC+ACID'>23E</scene>, <scene name='pdbligand=46F:(2R)-4-(6-CHLOROPYRIDAZIN-3-YL)-N-(4-METHOXYBENZYL)-1-{[4-(TRIFLUOROMETHOXY)PHENYL]SULFONYL}PIPERAZINE-2-CARBOXAMIDE'>46F</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=23E:(2E)-3-(4-{[(1-{[(13-CYCLOHEXYL-6-OXO-6,7-DIHYDRO-5H-INDOLO[1,2-D][1,4]BENZODIAZEPIN-10-YL)CARBONYL]AMINO}CYCLOPENTYL)CARBONYL]AMINO}PHENYL)PROP-2-ENOIC+ACID'>23E</scene>, <scene name='pdbligand=46F:(2R)-4-(6-CHLOROPYRIDAZIN-3-YL)-N-(4-METHOXYBENZYL)-1-{[4-(TRIFLUOROMETHOXY)PHENYL]SULFONYL}PIPERAZINE-2-CARBOXAMIDE'>46F</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3qgd\|3qgd]], [[3qge\|3qge]], [[3qgg\|3qgg]], [[3qgh\|3qgh]], [[3qgi\|3qgi]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qgd\|3qgd]], [[3qge\|3qge]], [[3qgg\|3qgg]], [[3qgh\|3qgh]], [[3qgi\|3qgi]]</div></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=31647 Hepatitis C virus subtype 1b])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS5B ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31647 Hepatitis C virus subtype 1b])</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [~~http~~://pdbe.org/3qgf PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3qgf PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgf 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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [https://pdbe.org/3qgf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [https://www.ebi.ac.uk/pdbsum/3qgf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgf ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/POLG_HCVCO POLG_HCVCO]] 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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 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 the host antiviral protein MAVS (By similarity). NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state.<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref>	+	[[https://www.uniprot.org/uniprot/POLG_HCVCO POLG_HCVCO]] 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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 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 the host antiviral protein MAVS (By similarity). NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state.<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 23:

	==See Also==		==See Also==
-	*[[RNA polymerase\|RNA polymerase]]	+	*[[RNA polymerase 3D structures\|RNA polymerase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 29:		Line 29:
	</StructureSection>		</StructureSection>
	[[Category: Hepatitis c virus subtype 1b]]		[[Category: Hepatitis c virus subtype 1b]]
		+	[[Category: Large Structures]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Sheriff, S]]		[[Category: Sheriff, S]]

OCA at 23:25, 4 August 2016

OCA — Thu, 04 Aug 2016 23:25:15 GMT

←Older revision		Revision as of 23:25, 4 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide==		==Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide==
	<StructureSection load='3qgf' size='340' side='right' caption='[[3qgf]], [[Resolution\|resolution]] 2.45Å' scene=''>		<StructureSection load='3qgf' size='340' side='right' caption='[[3qgf]], [[Resolution\|resolution]] 2.45Å' scene=''>
Line 7:		Line 8:
	<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=31647 Hepatitis C virus subtype 1b])</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=31647 Hepatitis C virus subtype 1b])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [http://www.ebi.ac.uk/pdbsum/3qgf 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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [http://pdbe.org/3qgf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [http://www.ebi.ac.uk/pdbsum/3qgf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qgf ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 20:
	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 3qgf" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 13:58, 25 December 2014

OCA — Thu, 25 Dec 2014 13:58:33 GMT

←Older revision		Revision as of 13:58, 25 December 2014
Line 9:		Line 9:
	<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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [http://www.ebi.ac.uk/pdbsum/3qgf 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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [http://www.ebi.ac.uk/pdbsum/3qgf PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/POLG_HCVCO POLG_HCVCO]] 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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 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 the host antiviral protein MAVS (By similarity). NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state.<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> 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).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:12702807</ref> <ref>PMID:15542681</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 13:19, 9 December 2014

OCA — Tue, 09 Dec 2014 13:19:24 GMT

←Older revision		Revision as of 13:19, 9 December 2014
Line 1:		Line 1:
-	[[~~Image:~~3qgf.~~png~~\|~~left~~\|~~200px~~]]	+	==Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide==
		+	<StructureSection load='3qgf' size='340' side='right' caption='[[3qgf]], [[Resolution\|resolution]] 2.45Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3qgf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QGF FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=23E:(2E)-3-(4-{[(1-{[(13-CYCLOHEXYL-6-OXO-6,7-DIHYDRO-5H-INDOLO[1,2-D][1,4]BENZODIAZEPIN-10-YL)CARBONYL]AMINO}CYCLOPENTYL)CARBONYL]AMINO}PHENYL)PROP-2-ENOIC+ACID'>23E</scene>, <scene name='pdbligand=46F:(2R)-4-(6-CHLOROPYRIDAZIN-3-YL)-N-(4-METHOXYBENZYL)-1-{[4-(TRIFLUOROMETHOXY)PHENYL]SULFONYL}PIPERAZINE-2-CARBOXAMIDE'>46F</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3qgd\|3qgd]], [[3qge\|3qge]], [[3qgg\|3qgg]], [[3qgh\|3qgh]], [[3qgi\|3qgi]]</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=31647 Hepatitis C virus subtype 1b])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </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=3qgf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qgf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qgf RCSB], [http://www.ebi.ac.uk/pdbsum/3qgf PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Structure based rationales for the activities of potent N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide inhibitors of the hepatitis C viral polymerase are described herein. These compounds bind to the hepatitis C virus non-structural protein 5B (NS5B), and co-crystal structures of select examples from this series with NS5B are reported. Comparison of co-crystal structures of a potent analog with both NS5B genotype 1a and genotype 1b provides a possible explanation for the genotype-selectivity observed with this compound class and suggests opportunities for the further optimization of the series.

-	~~{{STRUCTURE_3qgf\| PDB=3qgf \| SCENE= }}~~	+	Investigation of the mode of binding of a novel series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides to the hepatitis C virus polymerase.,Gentles RG, Sheriff S, Beno BR, Wan C, Kish K, Ding M, Zheng X, Chupak L, Poss MA, Witmer MR, Morin P, Wang YK, Rigat K, Lemm J, Voss S, Liu M, Pelosi L, Roberts SB, Gao M, Kadow JF Bioorg Med Chem Lett. 2011 Apr 15;21(8):2212-5. Epub 2011 Mar 6. PMID:21441029<ref>PMID:21441029</ref>

-	~~===Crystal structure~~ of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide===	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_21441029}}~~	+
-		+
-	~~==About this Structure==~~	+
-	~~[[3qgf]] is a 2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA].~~	+

	==See Also==		==See Also==
	*[[RNA polymerase\|RNA polymerase]]		*[[RNA polymerase\|RNA polymerase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	<~~ref group="xtra">PMID:021441029<~~/~~ref~~><~~references group="xtra"~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Hepatitis c virus subtype 1b]]		[[Category: Hepatitis c virus subtype 1b]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
-	[[Category: Sheriff, S.]]	+	[[Category: Sheriff, S]]
	[[Category: Finger]]		[[Category: Finger]]
	[[Category: Hcv]]		[[Category: Hcv]]

OCA at 17:32, 20 October 2012

OCA — Sat, 20 Oct 2012 17:32:16 GMT

←Older revision		Revision as of 17:32, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3qgf]] is a 2 chain structure ~~of [[RNA polymerase]]~~ with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA].	+	[[3qgf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA].

	==See Also==		==See Also==

OCA at 01:12, 27 July 2012

OCA — Fri, 27 Jul 2012 01:12:29 GMT

←Older revision		Revision as of 01:12, 27 July 2012
Line 1:		Line 1:
-	[[Image:3qgf.~~jpg~~\|left\|200px]]	+	[[Image:3qgf.png\|left\|200px]]

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-	-->
	{{STRUCTURE_3qgf\| PDB=3qgf \| SCENE= }}		{{STRUCTURE_3qgf\| PDB=3qgf \| SCENE= }}

	===Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide===		===Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_21441029}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 21441029 is the PubMed ID number.
-	-->
	{{ABSTRACT_PUBMED_21441029}}		{{ABSTRACT_PUBMED_21441029}}

	==About this Structure==		==About this Structure==
-	[[3qgf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA].	+	[[3qgf]] is a 2 chain structure of [[RNA polymerase]] with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA].
		+
		+	==See Also==
		+	*[[RNA polymerase\|RNA polymerase]]

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~21441029~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:021441029</ref><references group="xtra"/>
	[[Category: Hepatitis c virus subtype 1b]]		[[Category: Hepatitis c virus subtype 1b]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Sheriff, S.]]		[[Category: Sheriff, S.]]
		+	[[Category: Finger]]
		+	[[Category: Hcv]]
		+	[[Category: Ns5b]]
		+	[[Category: Palm]]
		+	[[Category: Polymerase]]
		+	[[Category: Thumb]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 10:39, 21 April 2011

OCA — Thu, 21 Apr 2011 10:39:08 GMT

←Older revision		Revision as of 10:39, 21 April 2011
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3qgf.jpg\|left\|200px]]

-	The ~~entry 3qgf~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3qgf", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_3qgf\| PDB=3qgf \| SCENE= }}

-	~~Authors: Sheriff~~, S.	+	===Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide===

-	~~Description: Crystal structure of the hepatitis C virus NS5B RNA~~-~~dependent RNA polymerase complex with (2E)-3-(4~~-{~~[(1-~~{[(~~13-cyclohexyl-6-oxo-6~~,7-~~dihydro~~-~~5H-indolo~~[1,2-d][~~1,4~~]~~benzodiazepin~~-~~10-yl)carbonyl~~]~~amino}cyclopentyl)carbonyl~~]~~amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{~~[~~4-(trifluoromethoxy)phenyl~~]~~sulfonyl}piperazine-2-carboxamide~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21441029}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21441029 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21441029}}
		+
		+	==About this Structure==
		+	[[3qgf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1b Hepatitis c virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QGF OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:21441029</ref><references group="xtra"/>
		+	[[Category: Hepatitis c virus subtype 1b]]
		+	[[Category: RNA-directed RNA polymerase]]
		+	[[Category: Sheriff, S.]]

OCA at 04:54, 13 April 2011

OCA — Wed, 13 Apr 2011 04:54:43 GMT

←Older revision		Revision as of 04:54, 13 April 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 3qgf is ON HOLD	+	The entry 3qgf is ON HOLD until Paper Publication

	Authors: Sheriff, S.		Authors: Sheriff, S.

	Description: Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide		Description: Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide

OCA at 09:37, 23 February 2011

OCA — Wed, 23 Feb 2011 09:37:43 GMT

←Older revision		Revision as of 09:37, 23 February 2011
Line 5:		Line 5:
	Authors: Sheriff, S.		Authors: Sheriff, S.

-	Description: ~~CRYSTAL STRUCTURE OF THE HEPATITIS~~ C ~~VIRUS~~ NS5B RNA-~~DEPENDENT~~ RNA ~~POLYMERASE COMPLEX WITH~~ (2E)-3-(4-{[(1-{[(13-~~CYCLOHEXYL~~-6-~~OXO~~-6,7-~~DIHYDRO~~-5H-~~INDOLO~~[1,2-D][1,4] ~~BENZODIAZEPIN~~-10-YL)~~CARBONYL~~]~~AMINO~~}~~CYCLOPENTYL~~)~~CARBONYL~~] ~~AMINO~~}~~PHENYL~~)-2-~~PROPENOIC ACID AND~~ 4-(6-~~CHLOROPYRIDAZIN~~-3-YL)-N-(4-~~METHOXYBENZYL~~)-1-(4-(~~TRIFLUOROMETHOXY~~) ~~PHENYLSULFONYL)PIPERAZINE~~-2-~~CARBOXAMIDE~~	+	Description: Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid and (2R)-4-(6-chloropyridazin-3-yl)-N-(4-methoxybenzyl)-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}piperazine-2-carboxamide