4ov6 - Revision history

OCA at 07:47, 25 January 2023

OCA — Wed, 25 Jan 2023 07:47:28 GMT

←Older revision		Revision as of 07:47, 25 January 2023
Line 1:		Line 1:

	==Crystal structure of PCSK9(53-451) with Adnectin==		==Crystal structure of PCSK9(53-451) with Adnectin==
-	<StructureSection load='4ov6' size='340' side='right' caption='[[4ov6]], [[Resolution\|resolution]] 2.69Å' scene=''>	+	<StructureSection load='4ov6' size='340' side='right'caption='[[4ov6]], [[Resolution\|resolution]] 2.69Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PCSK9, NARC1, PSEC0052 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [https://pdbe.org/4ov6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [https://www.ebi.ac.uk/pdbsum/4ov6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ov6 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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [~~http~~://pdbe.org/4ov6 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ov6 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ov6 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[~~http~~://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref>	+	[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[https://omim.org/entry/603776 603776]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref>	+	[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4ov6" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ov6" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[PCSK9\|PCSK9]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Khan, J A~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Adnectin]]~~	+	[[Category: Khan JA]]
-	~~[[Category: Hydrolase-protein binding complex]]~~	+
-	~~[[Category: Ldl-cholesterol]]~~	+
-	~~[[Category: Pcsk9~~]]	+

OCA at 08:30, 22 November 2017

OCA — Wed, 22 Nov 2017 08:30:52 GMT

←Older revision		Revision as of 08:30, 22 November 2017
Line 3:		Line 3:
	<StructureSection load='4ov6' size='340' side='right' caption='[[4ov6]], [[Resolution\|resolution]] 2.69Å' scene=''>		<StructureSection load='4ov6' size='340' side='right' caption='[[4ov6]], [[Resolution\|resolution]] 2.69Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PCSK9, NARC1, PSEC0052 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [http://pdbe.org/4ov6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [http://www.ebi.ac.uk/pdbsum/4ov6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ov6 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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [http://pdbe.org/4ov6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [http://www.ebi.ac.uk/pdbsum/4ov6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ov6 ProSAT]</span></td></tr>
	</table>		</table>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Khan, J A]]		[[Category: Khan, J A]]
	[[Category: Adnectin]]		[[Category: Adnectin]]

OCA at 15:20, 11 August 2016

OCA — Thu, 11 Aug 2016 15:20:39 GMT

←Older revision		Revision as of 15:20, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of PCSK9(53-451) with Adnectin==		==Crystal structure of PCSK9(53-451) with Adnectin==
	<StructureSection load='4ov6' size='340' side='right' caption='[[4ov6]], [[Resolution\|resolution]] 2.69Å' scene=''>		<StructureSection load='4ov6' size='340' side='right' caption='[[4ov6]], [[Resolution\|resolution]] 2.69Å' scene=''>
Line 4:		Line 5:
	<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [http://www.ebi.ac.uk/pdbsum/4ov6 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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [http://pdbe.org/4ov6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [http://www.ebi.ac.uk/pdbsum/4ov6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ov6 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
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 4ov6" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:43, 5 January 2015

OCA — Mon, 05 Jan 2015 12:43:42 GMT

←Older revision		Revision as of 12:43, 5 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [http://www.ebi.ac.uk/pdbsum/4ov6 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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [http://www.ebi.ac.uk/pdbsum/4ov6 PDBsum]</span></td></tr>
-	<table>	+	</table>
	== Disease ==		== Disease ==
	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref>		[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref>
Line 22:		Line 22:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Khan, J A.]]	+	[[Category: Khan, J A]]
	[[Category: Adnectin]]		[[Category: Adnectin]]
	[[Category: Hydrolase-protein binding complex]]		[[Category: Hydrolase-protein binding complex]]
	[[Category: Ldl-cholesterol]]		[[Category: Ldl-cholesterol]]
	[[Category: Pcsk9]]		[[Category: Pcsk9]]

OCA at 08:30, 2 July 2014

OCA — Wed, 02 Jul 2014 08:30:43 GMT

←Older revision		Revision as of 08:30, 2 July 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal structure of PCSK9(53-451) with Adnectin==
		+	<StructureSection load='4ov6' size='340' side='right' caption='[[4ov6]], [[Resolution\|resolution]] 2.69Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4ov6]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OV6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OV6 FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene><br>
		+	<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=4ov6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ov6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ov6 RCSB], [http://www.ebi.ac.uk/pdbsum/4ov6 PDBsum]</span></td></tr>
		+	<table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low density lipoprotein (LDL) in cardiovascular disease, though seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type-III-domain and engineered for high affinity target binding. BMS-962476, an ~11 kilodalton polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with sub-nanomolar affinity to human. The X-ray co-crystal structure of PCSK9 with a progenitor Adnectin shows ~910 A2 of PCSK9 surface covered next to the LDLR binding site, largely by residues of a single loop of the Adnectin. In hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels. In normal-expressing genomic transgenic mice, BMS-962476 potently reduced free human PCSK9 (ED50 ~0.01 mg/kg) followed by ~2-fold increases in total PCSK9 before return to baseline. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ~55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently down-regulated, following which LDL and total PCSK9 returned to baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL and liver cholesterol metabolism and characterize BMS-962476 as a potent and efficacious PCSK9 inhibitor.

-	~~The entry 4ov6 is ON HOLD until Paper Publication~~	+	Pharmacologic Profile of the Adnectin BMS-962476, a Small Protein Biologic Alternative to PCSK9 Antibodies for LDL Lowering.,Mitchell T, Chao G, Sitkoff D, Lo F, Monshizadegan H, Meyers D, Low S, Russo K, DiBella R, Denhez F, Gao M, Myers J, Duke G, Witmer M, Miao B, Ho SP, Khan J, Parker RA J Pharmacol Exp Ther. 2014 Jun 10. pii: jpet.114.214221. PMID:24917546<ref>PMID:24917546</ref>

-	~~Authors~~: Khan, J.A.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Crystal structure of PCSK9(53~~-~~451) with Adnectin~~	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Khan, J A.]]
		+	[[Category: Adnectin]]
		+	[[Category: Hydrolase-protein binding complex]]
		+	[[Category: Ldl-cholesterol]]
		+	[[Category: Pcsk9]]

OCA at 06:21, 30 April 2014

OCA — Wed, 30 Apr 2014 06:21:37 GMT

←Older revision		Revision as of 06:21, 30 April 2014
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4ov6 is ON HOLD	+	The entry 4ov6 is ON HOLD until Paper Publication

	Authors: Khan, J.A.		Authors: Khan, J.A.

	Description: Crystal structure of PCSK9(53-451) with Adnectin		Description: Crystal structure of PCSK9(53-451) with Adnectin

OCA: Protected "4ov6" [edit=sysop:move=sysop]

OCA — Mon, 03 Mar 2014 16:53:54 GMT

Protected "4ov6" [edit=sysop:move=sysop]

←Older revision

Revision as of 16:53, 3 March 2014

OCA: New page: '''Unreleased structure''' The entry 4ov6 is ON HOLD Authors: Khan, J.A. Description: Crystal structure of PCSK9(53-451) with Adnectin

OCA — Mon, 03 Mar 2014 16:53:53 GMT

New page: '''Unreleased structure''' The entry 4ov6 is ON HOLD Authors: Khan, J.A. Description: Crystal structure of PCSK9(53-451) with Adnectin

New page

'''Unreleased structure'''

The entry 4ov6 is ON HOLD

Authors: Khan, J.A.

Description: Crystal structure of PCSK9(53-451) with Adnectin