4mib - Revision history

OCA at 12:26, 1 March 2024

OCA — Fri, 01 Mar 2024 12:26:54 GMT

←Older revision		Revision as of 12:26, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_(isolate_BK) Hepatitis C virus (isolate BK)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MIB FirstGlance]. <br>		<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_(isolate_BK) Hepatitis C virus (isolate BK)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MIB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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]] 2.3Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [https://pdbe.org/4mib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [https://www.ebi.ac.uk/pdbsum/4mib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mib 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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [https://pdbe.org/4mib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [https://www.ebi.ac.uk/pdbsum/4mib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mib ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/POLG_HCVBK POLG_HCVBK] 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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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/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).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref>		[https://www.uniprot.org/uniprot/POLG_HCVBK POLG_HCVBK] 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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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/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).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
-
-	Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]pheny l]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.,Talamas FX, Abbot SC, Anand S, Brameld KA, Carter DS, Chen J, Davis D, de Vicente J, Fung AD, Gong L, Harris SF, Inbar P, Labadie SS, Lee EK, Lemoine R, Le Pogam S, Leveque V, Li J, McIntosh J, Najera I, Park J, Railkar A, Rajyaguru S, Sangi M, Schoenfeld RC, Staben LR, Tan Y, Taygerly JP, Villasenor AG, Weller PE J Med Chem. 2014 Mar 13;57(5):1914-31. doi: 10.1021/jm401329s. Epub 2013 Nov 6. PMID:24195700<ref>PMID:24195700</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4mib" style="background-color:#fffaf0;"></div>

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

OCA at 09:39, 28 December 2022

OCA — Wed, 28 Dec 2022 09:39:57 GMT

←Older revision		Revision as of 09:39, 28 December 2022
Line 3:		Line 3:
	<StructureSection load='4mib' size='340' side='right'caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='4mib' size='340' side='right'caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4mib]] 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=4MIB OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4MIB FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_(isolate_BK) Hepatitis C virus (isolate BK)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MIB FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [https://pdbe.org/4mib PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [https://www.ebi.ac.uk/pdbsum/4mib PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mib 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=11105 HCV])</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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [~~http~~://pdbe.org/4mib PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4mib PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4mib ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/POLG_HCVBK POLG_HCVBK]] 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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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/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).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref>	+	[https://www.uniprot.org/uniprot/POLG_HCVBK POLG_HCVBK] 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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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/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).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		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: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: RNA-directed RNA polymerase]]~~	+	[[Category: Harris SF]]
-	[[Category: Harris~~, S F~~]]	+	[[Category: Villasenor AG]]
-	[[Category: Villasenor~~, A G]]~~	+
-	~~[[Category: Ns5b]]~~	+
-	~~[[Category: Polymerase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:53, 10 April 2019

OCA — Wed, 10 Apr 2019 08:53:22 GMT

←Older revision		Revision as of 08:53, 10 April 2019
Line 1:		Line 1:

	==Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)==		==Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)==
-	<StructureSection load='4mib' size='340' side='right' caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>	+	<StructureSection load='4mib' size='340' side='right'caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MIB FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4mib]] 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=4MIB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MIB FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</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=11105 HCV])</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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://pdbe.org/4mib PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mib ProSAT]</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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://pdbe.org/4mib PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mib ProSAT]</span></td></tr>
Line 27:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Hcv]]
		+	[[Category: Large Structures]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Harris, S F]]		[[Category: Harris, S F]]

OCA at 06:12, 5 August 2016

OCA — Fri, 05 Aug 2016 06:12:39 GMT

←Older revision		Revision as of 06:12, 5 August 2016
Line 1:		Line 1:
		+
	==Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)==		==Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)==
	<StructureSection load='4mib' size='340' side='right' caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='4mib' size='340' side='right' caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib 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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://pdbe.org/4mib PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mib 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 4mib" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[RNA polymerase\|RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 23:43, 24 December 2014

OCA — Wed, 24 Dec 2014 23:43:38 GMT

←Older revision		Revision as of 23:43, 24 December 2014
Line 2:		Line 2:
	<StructureSection load='4mib' size='340' side='right' caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='4mib' size='340' side='right' caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. <br>	+	<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MIB FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</td></tr>
-	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/~~Glucokinase Glucokinase~~], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib 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=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib PDBsum]</span></td></tr>
-	<table>	+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/POLG_HCVBK POLG_HCVBK]] 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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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/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).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</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:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref> NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).<ref>PMID:9710605</ref> <ref>PMID:16530520</ref> <ref>PMID:17188392</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 14:		Line 16:
	Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]pheny l]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.,Talamas FX, Abbot SC, Anand S, Brameld KA, Carter DS, Chen J, Davis D, de Vicente J, Fung AD, Gong L, Harris SF, Inbar P, Labadie SS, Lee EK, Lemoine R, Le Pogam S, Leveque V, Li J, McIntosh J, Najera I, Park J, Railkar A, Rajyaguru S, Sangi M, Schoenfeld RC, Staben LR, Tan Y, Taygerly JP, Villasenor AG, Weller PE J Med Chem. 2014 Mar 13;57(5):1914-31. doi: 10.1021/jm401329s. Epub 2013 Nov 6. PMID:24195700<ref>PMID:24195700</ref>		Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]pheny l]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.,Talamas FX, Abbot SC, Anand S, Brameld KA, Carter DS, Chen J, Davis D, de Vicente J, Fung AD, Gong L, Harris SF, Inbar P, Labadie SS, Lee EK, Lemoine R, Le Pogam S, Leveque V, Li J, McIntosh J, Najera I, Park J, Railkar A, Rajyaguru S, Sangi M, Schoenfeld RC, Staben LR, Tan Y, Taygerly JP, Villasenor AG, Weller PE J Med Chem. 2014 Mar 13;57(5):1914-31. doi: 10.1021/jm401329s. Epub 2013 Nov 6. PMID:24195700<ref>PMID:24195700</ref>

-	From ~~MEDLINEÂ®~~/~~PubMedÂ®~~, 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>
	== References ==		== References ==
Line 21:		Line 23:
	</StructureSection>		</StructureSection>
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
-	[[Category: Harris, S F.]]	+	[[Category: Harris, S F]]
-	[[Category: Villasenor, A G.]]	+	[[Category: Villasenor, A G]]
	[[Category: Ns5b]]		[[Category: Ns5b]]
	[[Category: Polymerase]]		[[Category: Polymerase]]
	[[Category: Transferase]]		[[Category: Transferase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 08:15, 7 May 2014

OCA — Wed, 07 May 2014 08:15:55 GMT

←Older revision		Revision as of 08:15, 7 May 2014
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-	'''~~Unreleased~~ structure'''	+	==Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)==
		+	<StructureSection load='4mib' size='340' side='right' caption='[[4mib]], [[Resolution\|resolution]] 2.30Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mia\|4mia]], [[4mk7\|4mk7]], [[4mk8\|4mk8]], [[4mk9\|4mk9]], [[4mka\|4mka]], [[4mkb\|4mkb]]</td></tr>
		+	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.

-	~~The entry 4mib is ON HOLD until Paper Publication~~	+	Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]pheny l]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.,Talamas FX, Abbot SC, Anand S, Brameld KA, Carter DS, Chen J, Davis D, de Vicente J, Fung AD, Gong L, Harris SF, Inbar P, Labadie SS, Lee EK, Lemoine R, Le Pogam S, Leveque V, Li J, McIntosh J, Najera I, Park J, Railkar A, Rajyaguru S, Sangi M, Schoenfeld RC, Staben LR, Tan Y, Taygerly JP, Villasenor AG, Weller PE J Med Chem. 2014 Mar 13;57(5):1914-31. doi: 10.1021/jm401329s. Epub 2013 Nov 6. PMID:24195700<ref>PMID:24195700</ref>

-	~~Authors~~: Harris, S.F., Villasenor, A.G.	+	From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~:	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: RNA-directed RNA polymerase]]
		+	[[Category: Harris, S F.]]
		+	[[Category: Villasenor, A G.]]
		+	[[Category: Ns5b]]
		+	[[Category: Polymerase]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 06:56, 6 November 2013

OCA — Wed, 06 Nov 2013 06:56:43 GMT

←Older revision		Revision as of 06:56, 6 November 2013
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	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Harris, S.F., Villasenor, A.G.		Authors: Harris, S.F., Villasenor, A.G.

	Description:		Description:

OCA at 03:39, 20 September 2013

OCA — Fri, 20 Sep 2013 03:39:12 GMT

←Older revision		Revision as of 03:39, 20 September 2013
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	Authors: Harris, S.F., Villasenor, A.G.		Authors: Harris, S.F., Villasenor, A.G.

-	Description: ~~Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48~~	+	Description:

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

OCA — Thu, 12 Sep 2013 04:51:49 GMT

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

←Older revision

Revision as of 04:51, 12 September 2013

OCA: New page: '''Unreleased structure''' The entry 4mib is ON HOLD Authors: Harris, S.F., Villasenor, A.G. Description: Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48

OCA — Thu, 12 Sep 2013 04:51:48 GMT

New page: '''Unreleased structure''' The entry 4mib is ON HOLD Authors: Harris, S.F., Villasenor, A.G. Description: Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48

New page

'''Unreleased structure'''

The entry 4mib is ON HOLD

Authors: Harris, S.F., Villasenor, A.G.

Description: Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48