5pzk - Revision history

OCA at 13:28, 6 March 2024

OCA — Wed, 06 Mar 2024 13:28:34 GMT

←Older revision

Revision as of 13:28, 6 March 2024

OCA at 14:27, 24 January 2024

OCA — Wed, 24 Jan 2024 14:27:16 GMT

←Older revision		Revision as of 14:27, 24 January 2024
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	<StructureSection load='5pzk' size='340' side='right'caption='[[5pzk]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='5pzk' size='340' side='right'caption='[[5pzk]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5pzk]] 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=5PZK OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5PZK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5pzk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_(isolate_Con1) Hepatitis C virus (isolate Con1)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5PZK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5PZK 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=2N5:2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE'>2N5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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]] 2.2Å</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='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=2N5:2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE'>2N5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5pzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pzk OCA], [~~http~~://pdbe.org/5pzk PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5pzk RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5pzk PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5pzk 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=5pzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pzk OCA], [https://pdbe.org/5pzk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5pzk RCSB], [https://www.ebi.ac.uk/pdbsum/5pzk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5pzk 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 26:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Hcv]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: RNA-directed RNA polymerase]]~~	+	[[Category: Sheriff S]]
-	[[Category: Sheriff, S]]	+
-	~~[[Category: Finger]]~~	+
-	~~[[Category: Ns5b]]~~	+
-	~~[[Category: Palm]]~~	+
-	~~[[Category: Polymerase]]~~	+
-	~~[[Category: Thumb]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:54, 2 September 2020

OCA — Wed, 02 Sep 2020 07:54:08 GMT

←Older revision		Revision as of 07:54, 2 September 2020
Line 1:		Line 1:

	==CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA POLYMERASE IN COMPLEX WITH 2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE==		==CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA POLYMERASE IN COMPLEX WITH 2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE==
-	<StructureSection load='5pzk' size='340' side='right' caption='[[5pzk]], [[Resolution\|resolution]] 2.20Å' scene=''>	+	<StructureSection load='5pzk' size='340' side='right'caption='[[5pzk]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5pzk]] 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=5PZK OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5PZK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5pzk]] 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=5PZK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5PZK 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=2N5:2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE'>2N5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=2N5:2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE'>2N5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5pzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pzk OCA], [http://pdbe.org/5pzk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5pzk RCSB], [http://www.ebi.ac.uk/pdbsum/5pzk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5pzk ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5pzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pzk OCA], [http://pdbe.org/5pzk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5pzk RCSB], [http://www.ebi.ac.uk/pdbsum/5pzk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5pzk ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5pzk" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5pzk" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[RNA polymerase 3D structures\|RNA polymerase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 24:		Line 27:
	</StructureSection>		</StructureSection>
	[[Category: Hcv]]		[[Category: Hcv]]
		+	[[Category: Large Structures]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Sheriff, S]]		[[Category: Sheriff, S]]

OCA at 08:13, 22 February 2018

OCA — Thu, 22 Feb 2018 08:13:31 GMT

←Older revision		Revision as of 08:13, 22 February 2018
Line 3:		Line 3:
	<StructureSection load='5pzk' size='340' side='right' caption='[[5pzk]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='5pzk' size='340' side='right' caption='[[5pzk]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5pzk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5PZK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5PZK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5pzk]] 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=5PZK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5PZK 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=2N5:2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE'>2N5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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"><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=2N5:2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE'>2N5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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>
Line 23:		Line 23:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Hcv]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Sheriff, S]]		[[Category: Sheriff, S]]
	[[Category: Finger]]		[[Category: Finger]]
-	[[Category: Hcv]]
	[[Category: Ns5b]]		[[Category: Ns5b]]
	[[Category: Palm]]		[[Category: Palm]]

OCA at 12:54, 10 May 2017

OCA — Wed, 10 May 2017 12:54:34 GMT

←Older revision		Revision as of 12:54, 10 May 2017
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-	'''Unreleased structure'''

-	~~The entry~~ 5pzk is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENT RNA POLYMERASE IN COMPLEX WITH 2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE==
		+	<StructureSection load='5pzk' size='340' side='right' caption='[[5pzk]], [[Resolution\|resolution]] 2.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5pzk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5PZK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5PZK 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=2N5:2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE'>2N5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5pzk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5pzk OCA], [http://pdbe.org/5pzk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5pzk RCSB], [http://www.ebi.ac.uk/pdbsum/5pzk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5pzk ProSAT]</span></td></tr>
		+	</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;">
		+	== Publication Abstract from PubMed ==
		+	The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.

-	~~Authors: Sheriff~~, S.	+	Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.,Yeung KS, Beno BR, Parcella K, Bender JA, Grant-Young KA, Nickel A, Gunaga P, Anjanappa P, Bora RO, Selvakumar K, Rigat K, Wang YK, Liu M, Lemm J, Mosure K, Sheriff S, Wan C, Witmer M, Kish K, Hanumegowda U, Zhuo X, Shu YZ, Parker D, Haskell R, Ng A, Gao Q, Colston E, Raybon J, Grasela DM, Santone K, Gao M, Meanwell NA, Sinz M, Soars MG, Knipe JO, Roberts SB, Kadow JF J Med Chem. 2017 May 4. doi: 10.1021/acs.jmedchem.7b00328. PMID:28430437<ref>PMID:28430437</ref>

-	~~Description: CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA~~-~~DEPENDENTRNA POLYMERASE IN COMPLEX WITH 2~~-~~(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5pzk" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[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]]

OCA at 10:52, 27 April 2017

OCA — Thu, 27 Apr 2017 10:52:35 GMT

←Older revision		Revision as of 10:52, 27 April 2017
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5pzk is ON HOLD	+	The entry 5pzk is ON HOLD until Paper Publication

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

OCA: Protected "5pzk" [edit=sysop:move=sysop]

OCA — Thu, 09 Mar 2017 13:15:58 GMT

Protected "5pzk" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:15, 9 March 2017

OCA: New page: '''Unreleased structure''' The entry 5pzk is ON HOLD Authors: Sheriff, S. Description: CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENTRNA POLYMERASE IN COMPLEX WITH 2-(4-...

OCA — Thu, 09 Mar 2017 13:15:57 GMT

New page: '''Unreleased structure''' The entry 5pzk is ON HOLD Authors: Sheriff, S. Description: CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENTRNA POLYMERASE IN COMPLEX WITH 2-(4-...

New page

'''Unreleased structure'''

The entry 5pzk is ON HOLD

Authors: Sheriff, S.

Description: CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA-DEPENDENTRNA POLYMERASE IN COMPLEX WITH 2-(4-FLUOROPHENYL)-N-METHYL-6-[(METHYLSULFONYL)AMINO]-5-(PROPAN-2-YLOXY)-1-BENZOFURAN-3-CARBOXAMIDE
[[Category: Unreleased Structures]]
[[Category: Sheriff, S]]