6u36 - Revision history

OCA at 16:25, 29 January 2020

OCA — Wed, 29 Jan 2020 16:25:45 GMT

←Older revision		Revision as of 16:25, 29 January 2020
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	<StructureSection load='6u36' size='340' side='right'caption='[[6u36]], [[Resolution\|resolution]] 2.70Å' scene=''>		<StructureSection load='6u36' size='340' side='right'caption='[[6u36]], [[Resolution\|resolution]] 2.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6u36]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U36 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U36 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6u36]] is a 4 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=6U36 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U36 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PVM:2-fluoro-4-{[(1R)-6-(2-{4-[1-(4-methoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl]-1H-1,2,3-triazol-1-yl}ethoxy)-1-methyl-1-{2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]oxy}benzoic+acid'>PVM</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PVM:2-fluoro-4-{[(1R)-6-(2-{4-[1-(4-methoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl]-1H-1,2,3-triazol-1-yl}ethoxy)-1-methyl-1-{2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]oxy}benzoic+acid'>PVM</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=6u36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u36 OCA], [http://pdbe.org/6u36 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u36 RCSB], [http://www.ebi.ac.uk/pdbsum/6u36 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u36 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=6u36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u36 OCA], [http://pdbe.org/6u36 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u36 RCSB], [http://www.ebi.ac.uk/pdbsum/6u36 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u36 ProSAT]</span></td></tr>
	</table>		</table>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Lu, J]]		[[Category: Lu, J]]

OCA at 06:56, 6 November 2019

OCA — Wed, 06 Nov 2019 06:56:19 GMT

←Older revision		Revision as of 06:56, 6 November 2019
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-	'''Unreleased structure'''

-	~~The entry~~ 6u36 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==PCSK9 in complex with a Fab and compound 14==
		+	<StructureSection load='6u36' size='340' side='right'caption='[[6u36]], [[Resolution\|resolution]] 2.70Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6u36]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U36 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U36 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PVM:2-fluoro-4-{[(1R)-6-(2-{4-[1-(4-methoxyphenyl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl]-1H-1,2,3-triazol-1-yl}ethoxy)-1-methyl-1-{2-oxo-2-[(1,3-thiazol-2-yl)amino]ethyl}-1,2,3,4-tetrahydroisoquinolin-7-yl]oxy}benzoic+acid'>PVM</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=6u36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u36 OCA], [http://pdbe.org/6u36 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u36 RCSB], [http://www.ebi.ac.uk/pdbsum/6u36 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u36 ProSAT]</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 substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.

-	~~Authors~~: Lu, J., ~~Soisson~~, S.	+	From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.,Petrilli WL, Adam GC, Erdmann RS, Abeywickrema P, Agnani V, Ai X, Baysarowich J, Byrne N, Caldwell JP, Chang W, DiNunzio E, Feng Z, Ford R, Ha S, Huang Y, Hubbard B, Johnston JM, Kavana M, Lisnock JM, Liang R, Lu J, Lu Z, Meng J, Orth P, Palyha O, Parthasarathy G, Salowe SP, Sharma S, Shipman J, Soisson SM, Strack AM, Youm H, Zhao K, Zink DL, Zokian H, Addona GH, Akinsanya K, Tata JR, Xiong Y, Imbriglio JE Cell Chem Biol. 2019 Oct 22. pii: S2451-9456(19)30322-8. doi:, 10.1016/j.chembiol.2019.10.002. PMID:31653597<ref>PMID:31653597</ref>

-	~~Description: PCSK9 in complex with~~ a ~~Fab and compound 14~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	[[Category: ~~Soisson, S~~]]	+	<div class="pdbe-citations 6u36" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Lu, J]]		[[Category: Lu, J]]
		+	[[Category: Soisson, S]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase-immune system complex]]
		+	[[Category: Serine type endopeptidase activity proteolysis]]

OCA at 03:52, 10 October 2019

OCA — Thu, 10 Oct 2019 03:52:06 GMT

←Older revision		Revision as of 03:52, 10 October 2019
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6u36 is ON HOLD	+	The entry 6u36 is ON HOLD until Paper Publication

	Authors: Lu, J., Soisson, S.		Authors: Lu, J., Soisson, S.

OCA: Protected "6u36" [edit=sysop:move=sysop]

OCA — Wed, 28 Aug 2019 14:05:47 GMT

Protected "6u36" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:05, 28 August 2019

OCA: New page: '''Unreleased structure''' The entry 6u36 is ON HOLD Authors: Lu, J., Soisson, S. Description: PCSK9 in complex with a Fab and compound 14 Category: Unreleased Structures [[Categor...

OCA — Wed, 28 Aug 2019 14:05:45 GMT

New page: '''Unreleased structure''' The entry 6u36 is ON HOLD Authors: Lu, J., Soisson, S. Description: PCSK9 in complex with a Fab and compound 14 Category: Unreleased Structures [[Categor...

New page

'''Unreleased structure'''

The entry 6u36 is ON HOLD

Authors: Lu, J., Soisson, S.

Description: PCSK9 in complex with a Fab and compound 14
[[Category: Unreleased Structures]]
[[Category: Soisson, S]]
[[Category: Lu, J]]