3ske - Revision history

OCA at 07:59, 29 June 2022

OCA — Wed, 29 Jun 2022 07:59:45 GMT

←Older revision		Revision as of 07:59, 29 June 2022
Line 1:		Line 1:

	==I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles==		==I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles==
-	<StructureSection load='3ske' size='340' side='right' caption='[[3ske]], [[Resolution\|resolution]] 1.97Å' scene=''>	+	<StructureSection load='3ske' size='340' side='right'caption='[[3ske]], [[Resolution\|resolution]] 1.97Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3ske]] 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=3SKE OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3SKE FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3ske]] 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=3SKE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SKE FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=054:1-[(2-AMINOPYRIDIN-4-YL)METHYL]-3-(2,4-DIOXO-1,2-DIHYDROTHIENO[3,4-D]PYRIMIDIN-3(4H)-YL)-5-(TRIFLUOROMETHYL)-1H-INDOLE-2-CARBOXYLIC+ACID'>054</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=054:1-[(2-AMINOPYRIDIN-4-YL)METHYL]-3-(2,4-DIOXO-1,2-DIHYDROTHIENO[3,4-D]PYRIMIDIN-3(4H)-YL)-5-(TRIFLUOROMETHYL)-1H-INDOLE-2-CARBOXYLIC+ACID'>054</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">[[3ska\|3ska]], [[3skh\|3skh]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ska\|3ska]], [[3skh\|3skh]]</div></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=3ske FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ske OCA], [~~http~~://pdbe.org/3ske PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3ske RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3ske PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3ske 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=3ske FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ske OCA], [https://pdbe.org/3ske PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ske RCSB], [https://www.ebi.ac.uk/pdbsum/3ske PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ske ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity). E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves and inhibits the host antiviral protein MAVS (By similarity). NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).	+	[[https://www.uniprot.org/uniprot/POLG_HCVJ4 POLG_HCVJ4]] Core protein packages viral RNA to form a viral nucleocapsid, and promotes virion budding. Modulates viral translation initiation by interacting with HCV IRES and 40S ribosomal subunit. Also regulates many host cellular functions such as signaling pathways and apoptosis. Prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma signaling pathways and by inducing human STAT1 degradation. Thought to play a role in virus-mediated cell transformation leading to hepatocellular carcinomas. Interacts with, and activates STAT3 leading to cellular transformation. May repress the promoter of p53, and sequester CREB3 and SP110 isoform 3/Sp110b in the cytoplasm. Also represses cell cycle negative regulating factor CDKN1A, thereby interrupting an important check point of normal cell cycle regulation. Targets transcription factors involved in the regulation of inflammatory responses and in the immune response: suppresses NK-kappaB activation, and activates AP-1. Could mediate apoptotic pathways through association with TNF-type receptors TNFRSF1A and LTBR, although its effect on death receptor-induced apoptosis remains controversial. Enhances TRAIL mediated apoptosis, suggesting that it might play a role in immune-mediated liver cell injury. Seric core protein is able to bind C1QR1 at the T-cell surface, resulting in down-regulation of T-lymphocytes proliferation. May transactivate human MYC, Rous sarcoma virus LTR, and SV40 promoters. May suppress the human FOS and HIV-1 LTR activity. Alters lipid metabolism by interacting with hepatocellular proteins involved in lipid accumulation and storage. Core protein induces up-regulation of FAS promoter activity, and thereby probably contributes to the increased triglyceride accumulation in hepatocytes (steatosis) (By similarity). E1 and E2 glycoproteins form a heterodimer that is involved in virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. E1/E2 heterodimer binds to human LDLR, CD81 and SCARB1/SR-BI receptors, but this binding is not sufficient for infection, some additional liver specific cofactors may be needed. The fusion function may possibly be carried by E1. E2 inhibits human EIF2AK2/PKR activation, preventing the establishment of an antiviral state. E2 is a viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow capture of circulating HCV particles by these cells and subsequent transmission to permissive cells. DCs act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. Capture of circulating HCV particles by these SIGN+ cells may facilitate virus infection of proximal hepatocytes and lymphocyte subpopulations and may be essential for the establishment of persistent infection (By similarity). P7 seems to be a heptameric ion channel protein (viroporin) and is inhibited by the antiviral drug amantadine. Also inhibited by long-alkyl-chain iminosugar derivatives. Essential for infectivity (By similarity). Protease NS2-3 is a cysteine protease responsible for the autocatalytic cleavage of NS2-NS3. Seems to undergo self-inactivation following maturation (By similarity). NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS4A, is responsible for the cleavages of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. NS3/NS4A complex also prevents phosphorylation of human IRF3, thus preventing the establishment of dsRNA induced antiviral state. NS3 RNA helicase binds to RNA and unwinds dsRNA in the 3' to 5' direction, and likely RNA stable secondary structure in the template strand. Cleaves and inhibits the host antiviral protein MAVS (By similarity). NS4B induces a specific membrane alteration that serves as a scaffold for the virus replication complex. This membrane alteration gives rise to the so-called ER-derived membranous web that contains the replication complex (By similarity). NS5A is a component of the replication complex involved in RNA-binding. Its interaction with Human VAPB may target the viral replication complex to vesicles. Down-regulates viral IRES translation initiation. Mediates interferon resistance, presumably by interacting with and inhibiting human EIF2AK2/PKR. Seems to inhibit apoptosis by interacting with BIN1 and FKBP8. The hyperphosphorylated form of NS5A is an inhibitor of viral replication (By similarity). NS5B is a RNA-dependent RNA polymerase that plays an essential role in the virus replication (By similarity).
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 22:

	==See Also==		==See Also==
-	*[[RNA polymerase\|RNA polymerase]]	+	*[[RNA polymerase 3D structures\|RNA polymerase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 28:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Hcv]]		[[Category: Hcv]]
		+	[[Category: Large Structures]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Anilkumar, G N]]		[[Category: Anilkumar, G N]]

OCA at 18:01, 5 August 2016

OCA — Fri, 05 Aug 2016 18:01:27 GMT

←Older revision		Revision as of 18:01, 5 August 2016
Line 1:		Line 1:
		+
	==I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles==		==I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles==
	<StructureSection load='3ske' size='340' side='right' caption='[[3ske]], [[Resolution\|resolution]] 1.97Å' scene=''>		<StructureSection load='3ske' size='340' side='right' caption='[[3ske]], [[Resolution\|resolution]] 1.97Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3ske]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Viruses Viruses~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SKE FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3ske]] 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=3SKE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SKE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=054:1-[(2-AMINOPYRIDIN-4-YL)METHYL]-3-(2,4-DIOXO-1,2-DIHYDROTHIENO[3,4-D]PYRIMIDIN-3(4H)-YL)-5-(TRIFLUOROMETHYL)-1H-INDOLE-2-CARBOXYLIC+ACID'>054</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=054:1-[(2-AMINOPYRIDIN-4-YL)METHYL]-3-(2,4-DIOXO-1,2-DIHYDROTHIENO[3,4-D]PYRIMIDIN-3(4H)-YL)-5-(TRIFLUOROMETHYL)-1H-INDOLE-2-CARBOXYLIC+ACID'>054</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">[[3ska\|3ska]], [[3skh\|3skh]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ska\|3ska]], [[3skh\|3skh]]</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=3ske FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ske OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ske RCSB], [http://www.ebi.ac.uk/pdbsum/3ske 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=3ske FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ske OCA], [http://pdbe.org/3ske PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ske RCSB], [http://www.ebi.ac.uk/pdbsum/3ske PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ske 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 3ske" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Hcv]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
-	[[Category: Viruses]]
	[[Category: Anilkumar, G N]]		[[Category: Anilkumar, G N]]
	[[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 20:49, 25 December 2014

OCA — Thu, 25 Dec 2014 20:49:12 GMT

←Older revision		Revision as of 20:49, 25 December 2014
Line 8:		Line 8:
	<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=3ske FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ske OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ske RCSB], [http://www.ebi.ac.uk/pdbsum/3ske 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=3ske FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ske OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ske RCSB], [http://www.ebi.ac.uk/pdbsum/3ske 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 ==

OCA at 13:41, 9 December 2014

OCA — Tue, 09 Dec 2014 13:41:29 GMT

←Older revision		Revision as of 13:41, 9 December 2014
Line 1:		Line 1:
-	[[~~Image:~~3ske.~~png~~\|~~left~~\|~~200px~~]]	+	==I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles==
		+	<StructureSection load='3ske' size='340' side='right' caption='[[3ske]], [[Resolution\|resolution]] 1.97Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3ske]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Viruses Viruses]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SKE FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=054:1-[(2-AMINOPYRIDIN-4-YL)METHYL]-3-(2,4-DIOXO-1,2-DIHYDROTHIENO[3,4-D]PYRIMIDIN-3(4H)-YL)-5-(TRIFLUOROMETHYL)-1H-INDOLE-2-CARBOXYLIC+ACID'>054</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">[[3ska\|3ska]], [[3skh\|3skh]]</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=3ske FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ske OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ske RCSB], [http://www.ebi.ac.uk/pdbsum/3ske PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9muM, replicon EC(50)>100muM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032muM, replicon EC(50)=1.4muM) and 7r (NS5B IC(50)=0.017muM, replicon EC(50)=0.3muM) with improved enzyme and replicon activity.

-	~~{{STRUCTURE_3ske\| PDB=3ske \| SCENE= }}~~	+	I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles.,Anilkumar GN, Lesburg CA, Selyutin O, Rosenblum SB, Zeng Q, Jiang Y, Chan TY, Pu H, Vaccaro H, Wang L, Bennett F, Chen KX, Duca J, Gavalas S, Huang Y, Pinto P, Sannigrahi M, Velazquez F, Venkatraman S, Vibulbhan B, Agrawal S, Butkiewicz N, Feld B, Ferrari E, He Z, Jiang CK, Palermo RE, McMonagle P, Huang HC, Shih NY, Njoroge G, Kozlowski JA Bioorg Med Chem Lett. 2011 Sep 15;21(18):5336-41. Epub 2011 Jul 19. PMID:21840715<ref>PMID:21840715</ref>

-	~~===I. Novel HCV NS5B Polymerase Inhibitors: Discovery~~ of ~~Indole 2- Carboxylic Acids with C3-Heterocycles===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~{{ABSTRACT_PUBMED_21840715}}~~	+
-		+
-	~~==About this Structure==~~	+
-	~~[[3ske]] is a 2 chain structure with sequence from [http://en~~.~~wikipedia~~.~~org/wiki/Viruses Viruses]~~. ~~Full crystallographic information is available from [http:~~/~~/oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA].~~	+

	==See Also==		==See Also==
	*[[RNA polymerase\|RNA polymerase]]		*[[RNA polymerase\|RNA polymerase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	<~~ref group="xtra">PMID:021840715<~~/~~ref~~><~~references group="xtra"~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Viruses]]		[[Category: Viruses]]
-	[[Category: Anilkumar, G N.]]	+	[[Category: Anilkumar, G N]]
-	[[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 21:27, 20 October 2012

OCA — Sat, 20 Oct 2012 21:27:42 GMT

←Older revision		Revision as of 21:27, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3ske]] is a 2 chain structure ~~of [[RNA polymerase]]~~ with sequence from [http://en.wikipedia.org/wiki/Viruses Viruses]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA].	+	[[3ske]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Viruses Viruses]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA].

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

OCA at 13:19, 27 July 2012

OCA — Fri, 27 Jul 2012 13:19:38 GMT

←Older revision		Revision as of 13:19, 27 July 2012
Line 1:		Line 1:
-	[[Image:3ske.~~jpg~~\|left\|200px]]	+	[[Image:3ske.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3ske", 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_3ske\| PDB=3ske \| SCENE= }}		{{STRUCTURE_3ske\| PDB=3ske \| SCENE= }}

	===I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles===		===I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_21840715}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 21840715 is the PubMed ID number.
-	-->
	{{ABSTRACT_PUBMED_21840715}}		{{ABSTRACT_PUBMED_21840715}}

	==About this Structure==		==About this Structure==
-	[[3ske]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Viruses Viruses]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA].	+	[[3ske]] is a 2 chain structure of [[RNA polymerase]] with sequence from [http://en.wikipedia.org/wiki/Viruses Viruses]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA].
		+
		+	==See Also==
		+	*[[RNA polymerase\|RNA polymerase]]

	==Reference==		==Reference==

OCA at 06:46, 31 August 2011

OCA — Wed, 31 Aug 2011 06:46:26 GMT

←Older revision		Revision as of 06:46, 31 August 2011
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3ske.jpg\|left\|200px]]

-	The ~~entry 3ske~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3ske", 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_3ske\| PDB=3ske \| SCENE= }}

-	~~Authors~~: ~~Lesburg, C.A., Anilkumar, G.N.~~	+	===I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles===

-	~~Description~~: I. ~~Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2~~-~~Carboxylic Acids~~ with C3-~~Heterocycles~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21840715}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21840715 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21840715}}
		+
		+	==About this Structure==
		+	[[3ske]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Viruses Viruses]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SKE OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021840715</ref><references group="xtra"/>
		+	[[Category: RNA-directed RNA polymerase]]
		+	[[Category: Viruses]]
		+	[[Category: Anilkumar, G N.]]
		+	[[Category: Lesburg, C A.]]
		+	[[Category: Rna-dependent rna polymerase]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 05:39, 27 July 2011

OCA — Wed, 27 Jul 2011 05:39:31 GMT

←Older revision		Revision as of 05:39, 27 July 2011
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Lesburg, C.A., Anilkumar, G.N.		Authors: Lesburg, C.A., Anilkumar, G.N.

	Description: I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2-Carboxylic Acids with C3-Heterocycles		Description: I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2-Carboxylic Acids with C3-Heterocycles

OCA: Protected "3ske" [edit=sysop:move=sysop]

OCA — Wed, 29 Jun 2011 05:48:02 GMT

Protected "3ske" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:48, 29 June 2011

OCA: New page: '''Unreleased structure''' The entry 3ske is ON HOLD Authors: Lesburg, C.A., Anilkumar, G.N. Description: I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2-Carboxylic Acid...

OCA — Wed, 29 Jun 2011 05:48:01 GMT

New page: '''Unreleased structure''' The entry 3ske is ON HOLD Authors: Lesburg, C.A., Anilkumar, G.N. Description: I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2-Carboxylic Acid...

New page

'''Unreleased structure'''

The entry 3ske is ON HOLD

Authors: Lesburg, C.A., Anilkumar, G.N.

Description: I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2-Carboxylic Acids with C3-Heterocycles