4ry7 - Revision history

OCA at 17:58, 20 September 2023

OCA — Wed, 20 Sep 2023 17:58:38 GMT

←Older revision		Revision as of 17:58, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ry7]] 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=4RY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RY7 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ry7]] 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=4RY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RY7 FirstGlance]. <br>
-	</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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [https://pdbe.org/4ry7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [https://www.ebi.ac.uk/pdbsum/4ry7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ry7 ProSAT]</span></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]] 3Å</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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [https://pdbe.org/4ry7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [https://www.ebi.ac.uk/pdbsum/4ry7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ry7 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==

OCA at 10:33, 15 March 2023

OCA — Wed, 15 Mar 2023 10:33:38 GMT

←Older revision		Revision as of 10:33, 15 March 2023
Line 1:		Line 1:

	==C-terminal mutant (D559E) of HCV/J4 RNA polymerase==		==C-terminal mutant (D559E) of HCV/J4 RNA polymerase==
-	<StructureSection load='4ry7' size='340' side='right' caption='[[4ry7]], [[Resolution\|resolution]] 3.00Å' scene=''>	+	<StructureSection load='4ry7' size='340' side='right'caption='[[4ry7]], [[Resolution\|resolution]] 3.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ry7]] 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=4RY7 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4RY7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ry7]] 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=4RY7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RY7 FirstGlance]. <br>
-	</td></tr>~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1nb4\|1nb4]], [[4ry4\|4ry4]], [[4ry5\|4ry5]], [[4ry6\|4ry6]]</td></tr>~~	+	</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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [https://pdbe.org/4ry7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [https://www.ebi.ac.uk/pdbsum/4ry7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ry7 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=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='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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [~~http~~://pdbe.org/4ry7 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ry7 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ry7 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 ==
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	</div>		</div>
	<div class="pdbe-citations 4ry7" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ry7" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[RNA polymerase 3D structures\|RNA polymerase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Hcv~~]]	+	[[Category: Hepatitis C virus isolate HC-J4]]
-	[[Category: ~~RNA-directed RNA polymerase~~]]	+	[[Category: Large Structures]]
-	[[Category: Cherry, A]]	+	[[Category: Cherry A]]
-	[[Category: Dennis, C]]	+	[[Category: Dennis C]]
-	[[Category: Jaeger, J]]	+	[[Category: Jaeger J]]
-	~~[[Category: Function analysis]]~~	+
-	~~[[Category: Hepatitis c virus]]~~	+
-	~~[[Category: Nucleotide transfer]]~~	+
-	~~[[Category: Rdrp]]~~	+
-	~~[[Category: Replication]]~~	+
-	~~[[Category: Rna rntp mg]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Viral rna polymerase~~]]	+

OCA at 09:12, 22 November 2017

OCA — Wed, 22 Nov 2017 09:12:12 GMT

←Older revision		Revision as of 09:12, 22 November 2017
Line 3:		Line 3:
	<StructureSection load='4ry7' size='340' side='right' caption='[[4ry7]], [[Resolution\|resolution]] 3.00Å' scene=''>		<StructureSection load='4ry7' size='340' side='right' caption='[[4ry7]], [[Resolution\|resolution]] 3.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ry7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RY7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RY7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ry7]] 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=4RY7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RY7 FirstGlance]. <br>
	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1nb4\|1nb4]], [[4ry4\|4ry4]], [[4ry5\|4ry5]], [[4ry6\|4ry6]]</td></tr>		</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1nb4\|1nb4]], [[4ry4\|4ry4]], [[4ry5\|4ry5]], [[4ry6\|4ry6]]</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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [http://pdbe.org/4ry7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ry7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ry7 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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [http://pdbe.org/4ry7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ry7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ry7 ProSAT]</span></td></tr>
Line 19:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4ry7" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ry7" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[RNA polymerase\|RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Hcv]]
	[[Category: RNA-directed RNA polymerase]]		[[Category: RNA-directed RNA polymerase]]
	[[Category: Cherry, A]]		[[Category: Cherry, A]]

OCA at 01:18, 19 January 2017

OCA — Thu, 19 Jan 2017 01:18:25 GMT

←Older revision		Revision as of 01:18, 19 January 2017
Line 1:		Line 1:
		+
	==C-terminal mutant (D559E) of HCV/J4 RNA polymerase==		==C-terminal mutant (D559E) of HCV/J4 RNA polymerase==
	<StructureSection load='4ry7' size='340' side='right' caption='[[4ry7]], [[Resolution\|resolution]] 3.00Å' scene=''>		<StructureSection load='4ry7' size='340' side='right' caption='[[4ry7]], [[Resolution\|resolution]] 3.00Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1nb4\|1nb4]], [[4ry4\|4ry4]], [[4ry5\|4ry5]], [[4ry6\|4ry6]]</td></tr>		</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1nb4\|1nb4]], [[4ry4\|4ry4]], [[4ry5\|4ry5]], [[4ry6\|4ry6]]</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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ry7 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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [http://pdbe.org/4ry7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ry7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ry7 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 17:		Line 18:
	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 4ry7" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[RNA polymerase\|RNA polymerase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 14:46, 31 December 2014

OCA — Wed, 31 Dec 2014 14:46:18 GMT

←Older revision		Revision as of 14:46, 31 December 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==C-terminal mutant (D559E) of HCV/J4 RNA polymerase==
		+	<StructureSection load='4ry7' size='340' side='right' caption='[[4ry7]], [[Resolution\|resolution]] 3.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4ry7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RY7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RY7 FirstGlance]. <br>
		+	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1nb4\|1nb4]], [[4ry4\|4ry4]], [[4ry5\|4ry5]], [[4ry6\|4ry6]]</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=4ry7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ry7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ry7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ry7 PDBsum]</span></td></tr>
		+	</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;">
		+	== Publication Abstract from PubMed ==
		+	The RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) is essential for viral genome replication. Crystal structures of the HCV RdRp reveal two C-terminal features, a beta-loop and a C-terminal arm, suitably located for involvement in positioning components of the initiation complex. Here we show that these two elements intimately regulate template and nucleotide binding, initiation and elongation. We constructed a series of beta-loop and C-terminal arm mutants, which were used for in vitro analysis of RdRp de novo initiation and primer extension activities. All mutants showed a substantial decrease in initiation assays but a marked increase in primer extension activities indicating an ability to form more stable elongation complexes with long primer:template RNAs. Structural studies of the mutants indicated that these enzyme properties might be attributed to an increased flexibility in the C-terminal features resulting in a more open polymerase cleft, which likely favours the elongation process but hampers the initiation steps. A UTP co-crystal structure of one mutant shows, in contrast to wild type protein, several alternate conformations of the substrate confirming that even subtle changes in the C-terminal arm result in a more loosely organized active site and flexible binding modes of the nucleotide. We used a sub-genomic replicon system to assess the effects of the same mutations on viral replication in cells. Even the subtlest mutations either severely impaired or completely abolished the ability of the replicon to replicate, further supporting the concept that correct positioning of both the beta-loop and C-terminal arm play an essential role during initiation and in HCV replication in general. IMPORTANCE: HCV RNA polymerase is a key target for the development of directly acting agents to cure HCV infections and necessitates a thorough understanding of the functional roles of the various structural features on the RdRp. Here we show that even highly conservative changes, e.g. Tyr --> Phe or Asp --> Glu, in these seemingly peripheral structural features have profound effects on the initiation and elongation properties of the HCV polymerase.

-	~~The entry 4ry7 is ON HOLD~~	+	HYDROPHOBIC AND CHARGED RESIDUES IN THE C-TERMINAL ARM OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE REGULATE INITIATION AND ELONGATION.,Cherry AL, Dennis CA, Baron A, Eisele LE, Thommes PA, Jaeger J J Virol. 2014 Nov 26. pii: JVI.01106-14. PMID:25428878<ref>PMID:25428878</ref>

-	~~Authors: Jaeger~~, J.~~, Cherry, A~~.~~, Dennis, C~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description:~~	+	== References ==
-	[[Category: ~~Unreleased Structures~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: RNA-directed RNA polymerase]]
	[[Category: Cherry, A]]		[[Category: Cherry, A]]
	[[Category: Dennis, C]]		[[Category: Dennis, C]]
	[[Category: Jaeger, J]]		[[Category: Jaeger, J]]
		+	[[Category: Function analysis]]
		+	[[Category: Hepatitis c virus]]
		+	[[Category: Nucleotide transfer]]
		+	[[Category: Rdrp]]
		+	[[Category: Replication]]
		+	[[Category: Rna rntp mg]]
		+	[[Category: Transferase]]
		+	[[Category: Viral rna polymerase]]

OCA at 17:36, 24 December 2014

OCA — Wed, 24 Dec 2014 17:36:26 GMT

←Older revision		Revision as of 17:36, 24 December 2014
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	Authors: Jaeger, J., Cherry, A., Dennis, C.		Authors: Jaeger, J., Cherry, A., Dennis, C.

-	Description:	+	Description:
		+	[[Category: Unreleased Structures]]
		+	[[Category: Cherry, A]]
		+	[[Category: Dennis, C]]
		+	[[Category: Jaeger, J]]

OCA: Protected "4ry7" [edit=sysop:move=sysop]

OCA — Wed, 24 Dec 2014 09:32:23 GMT

Protected "4ry7" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:32, 24 December 2014

OCA: New page: '''Unreleased structure''' The entry 4ry7 is ON HOLD Authors: Jaeger, J., Cherry, A., Dennis, C. Description:

OCA — Wed, 24 Dec 2014 09:32:22 GMT

New page: '''Unreleased structure''' The entry 4ry7 is ON HOLD Authors: Jaeger, J., Cherry, A., Dennis, C. Description:

New page

'''Unreleased structure'''

The entry 4ry7 is ON HOLD

Authors: Jaeger, J., Cherry, A., Dennis, C.

Description: