3tyv - Revision history

OCA at 12:14, 6 March 2024

OCA — Wed, 06 Mar 2024 12:14:23 GMT

←Older revision		Revision as of 12:14, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='3tyv' size='340' side='right'caption='[[3tyv]], [[Resolution\|resolution]] 1.65Å' scene=''>		<StructureSection load='3tyv' size='340' side='right'caption='[[3tyv]], [[Resolution\|resolution]] 1.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3tyv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Hcv Hcv~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TYV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3tyv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_C_virus_isolate_HC-J4 Hepatitis C virus isolate HC-J4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TYV FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.65Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3tyq\|3tyq]]</div></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=420174 HCV])</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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [https://pdbe.org/3tyv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [https://www.ebi.ac.uk/pdbsum/3tyv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tyv 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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [https://pdbe.org/3tyv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [https://www.ebi.ac.uk/pdbsum/3tyv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tyv ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity). E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves and inhibits the host antiviral protein MAVS (By similarity). NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).	+	[https://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4] Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity). E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves and inhibits the host antiviral protein MAVS (By similarity). NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 muM) and cell-based replicon (EC(50) = 0.02 muM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 muM.h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.	+
-		+
-	Structure-Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase.,Chen KX, Vibulbhan B, Yang W, Sannigrahi M, Velazquez F, Chan TY, Venkatraman S, Anilkumar GN, Zeng Q, Bennet F, Jiang Y, Lesburg CA, Duca J, Pinto P, Gavalas S, Huang Y, Wu W, Selyutin O, Agrawal S, Feld B, Huang HC, Li C, Cheng KC, Shih NY, Kozlowski JA, Rosenblum SB, Njoroge FG J Med Chem. 2012 Jan 26;55(2):754-65. Epub 2012 Jan 6. PMID:22148957<ref>PMID:22148957</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3tyv" style="background-color:#fffaf0;"></div>~~	+

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

OCA at 05:50, 13 July 2022

OCA — Wed, 13 Jul 2022 05:50:51 GMT

←Older revision		Revision as of 05:50, 13 July 2022
Line 1:		Line 1:

	==SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase==		==SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase==
-	<StructureSection load='3tyv' size='340' side='right' caption='[[3tyv]], [[Resolution\|resolution]] 1.65Å' scene=''>	+	<StructureSection load='3tyv' size='340' side='right'caption='[[3tyv]], [[Resolution\|resolution]] 1.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3tyv]] 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=3TYV OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3TYV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3tyv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hcv Hcv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TYV FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3tyq\|3tyq]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3tyq\|3tyq]]</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=420174 HCV])</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=420174 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'>[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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [~~http~~://pdbe.org/3tyv PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3tyv PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3tyv 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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [https://pdbe.org/3tyv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [https://www.ebi.ac.uk/pdbsum/3tyv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tyv ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity). E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves and inhibits the host antiviral protein MAVS (By similarity). NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).	+	[[https://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity). E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves and inhibits the host antiviral protein MAVS (By similarity). NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 3tyv" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3tyv" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[RNA polymerase 3D structures\|RNA polymerase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 26:		Line 29:
	</StructureSection>		</StructureSection>
	[[Category: Hcv]]		[[Category: Hcv]]
		+	[[Category: Large Structures]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Chen, K X]]		[[Category: Chen, K X]]

OCA at 09:57, 8 November 2017

OCA — Wed, 08 Nov 2017 09:57:45 GMT

←Older revision		Revision as of 09:57, 8 November 2017
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 3tyv" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3tyv" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[RNA polymerase\|RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 15:30, 4 August 2016

OCA — Thu, 04 Aug 2016 15:30:33 GMT

←Older revision		Revision as of 15:30, 4 August 2016
Line 1:		Line 1:
		+
	==SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase==		==SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase==
	<StructureSection load='3tyv' size='340' side='right' caption='[[3tyv]], [[Resolution\|resolution]] 1.65Å' scene=''>		<StructureSection load='3tyv' size='340' side='right' caption='[[3tyv]], [[Resolution\|resolution]] 1.65Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3tyv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Hepatitis_c_virus Hepatitis c virus~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TYV FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3tyv]] 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=3TYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TYV FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3tyq\|3tyq]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3tyq\|3tyq]]</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=~~11103 Hepatitis C virus~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NS5B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=420174 HCV])</td></tr>
	<tr id='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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [http://www.ebi.ac.uk/pdbsum/3tyv 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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [http://pdbe.org/3tyv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [http://www.ebi.ac.uk/pdbsum/3tyv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3tyv 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 3tyv" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[RNA polymerase\|RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Hepatitis c virus~~]]	+	[[Category: Hcv]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Chen, K X]]		[[Category: Chen, K X]]

OCA at 16:26, 24 December 2014

OCA — Wed, 24 Dec 2014 16:26:27 GMT

←Older revision		Revision as of 16:26, 24 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3tyv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TYV FirstGlance]. <br>		<table><tr><td colspan='2'>[[3tyv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TYV FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3tyq\|3tyq]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3tyq\|3tyq]]</td></tr>
-	<tr><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=11103 Hepatitis C virus])</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=11103 Hepatitis C virus])</td></tr>
-	<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [http://www.ebi.ac.uk/pdbsum/3tyv 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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [http://www.ebi.ac.uk/pdbsum/3tyv PDBsum]</span></td></tr>
-	<table>	+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity). E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves and inhibits the host antiviral protein MAVS (By similarity). NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 25:
	[[Category: Hepatitis c virus]]		[[Category: Hepatitis c virus]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
-	[[Category: Chen, K X.]]	+	[[Category: Chen, K X]]
-	[[Category: Lesburg, C A.]]	+	[[Category: Lesburg, C A]]
	[[Category: Rna-dependent rna polymerase]]		[[Category: Rna-dependent rna polymerase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 09:24, 11 June 2014

OCA — Wed, 11 Jun 2014 09:24:36 GMT

←Older revision		Revision as of 09:24, 11 June 2014
Line 1:		Line 1:
-	[[~~Image:~~3tyv.~~png~~\|~~left~~\|~~200px~~]]	+	==SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase==
		+	<StructureSection load='3tyv' size='340' side='right' caption='[[3tyv]], [[Resolution\|resolution]] 1.65Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3tyv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TYV FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HI3:N-(CYCLOPROPYLSULFONYL)-1-(2,5-DIFLUOROBENZYL)-6-FLUORO-5-METHYL-3-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)-1H-INDOLE-2-CARBOXAMIDE'>HI3</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3tyq\|3tyq]]</td></tr>
		+	<tr><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=11103 Hepatitis C virus])</td></tr>
		+	<tr><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=3tyv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tyv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tyv RCSB], [http://www.ebi.ac.uk/pdbsum/3tyv PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 muM) and cell-based replicon (EC(50) = 0.02 muM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 muM.h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.

-	~~{{STRUCTURE_3tyv\| PDB=3tyv \| SCENE= }}~~	+	Structure-Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase.,Chen KX, Vibulbhan B, Yang W, Sannigrahi M, Velazquez F, Chan TY, Venkatraman S, Anilkumar GN, Zeng Q, Bennet F, Jiang Y, Lesburg CA, Duca J, Pinto P, Gavalas S, Huang Y, Wu W, Selyutin O, Agrawal S, Feld B, Huang HC, Li C, Cheng KC, Shih NY, Kozlowski JA, Rosenblum SB, Njoroge FG J Med Chem. 2012 Jan 26;55(2):754-65. Epub 2012 Jan 6. PMID:22148957<ref>PMID:22148957</ref>

-	~~===SAR development and discovery of potent indole-based inhibitors~~ of the ~~hepatitis C virus NS5B polymerase===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_22148957}}~~	+	== References ==
-		+	<references/>
-	~~==About this Structure==~~	+	__TOC__
-	~~[[3tyv]] is a 2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Hepatitis_c_virus Hepatitis c virus]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA].~~	+	</StructureSection>
-		+
-	==~~Reference~~==	+
-	<~~ref group="xtra">PMID:022148957<~~/~~ref~~><~~references group="xtra"~~/>	+
	[[Category: Hepatitis c virus]]		[[Category: Hepatitis c virus]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]

OCA at 10:24, 8 August 2012

OCA — Wed, 08 Aug 2012 10:24:07 GMT

←Older revision		Revision as of 10:24, 8 August 2012
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	[[Image:3tyv.png\|left\|200px]]		[[Image:3tyv.png\|left\|200px]]

-	<!--
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-	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.
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	{{STRUCTURE_3tyv\| PDB=3tyv \| SCENE= }}		{{STRUCTURE_3tyv\| PDB=3tyv \| SCENE= }}

	===SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase===		===SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase===

-
-	<!--
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	{{ABSTRACT_PUBMED_22148957}}		{{ABSTRACT_PUBMED_22148957}}

OCA at 05:42, 8 February 2012

OCA — Wed, 08 Feb 2012 05:42:48 GMT

←Older revision		Revision as of 05:42, 8 February 2012
Line 1:		Line 1:
-	[[Image:3tyv.~~jpg~~\|left\|200px]]	+	[[Image:3tyv.png\|left\|200px]]

	<!--		<!--

OCA at 07:21, 1 February 2012

OCA — Wed, 01 Feb 2012 07:21:02 GMT

←Older revision		Revision as of 07:21, 1 February 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3tyv.jpg\|left\|200px]]

-	The ~~entry 3tyv~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3tyv", 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_3tyv\| PDB=3tyv \| SCENE= }}

-	~~Authors: Lesburg,~~ C~~.A., Chen, K.X.~~	+	===SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase===

-	~~Description: SAR development and discovery of potent indole~~-~~based inhibitors of~~ the ~~hepatitis C~~ virus ~~NS5B~~ polymerase	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_22148957}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 22148957 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_22148957}}
		+
		+	==About this Structure==
		+	[[3tyv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TYV OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:022148957</ref><references group="xtra"/>
		+	[[Category: Hepatitis c virus]]
		+	[[Category: RNA-directed RNA polymerase]]
		+	[[Category: Chen, K X.]]
		+	[[Category: Lesburg, C A.]]
		+	[[Category: Rna-dependent rna polymerase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 18:33, 23 November 2011

OCA — Wed, 23 Nov 2011 18:33:05 GMT

←Older revision		Revision as of 18:33, 23 November 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Lesburg, C.A., Chen, K.X.		Authors: Lesburg, C.A., Chen, K.X.

	Description: SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase		Description: SAR development and discovery of potent indole-based inhibitors of the hepatitis C virus NS5B polymerase