5vla - Revision history

OCA at 13:50, 4 October 2023

2023-10-04T13:50:53Z

←Older revision		Revision as of 13:50, 4 October 2023
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	<StructureSection load='5vla' size='340' side='right'caption='[[5vla]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='5vla' size='340' side='right'caption='[[5vla]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5vla]] is a 2 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=5VLA OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5VLA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5vla]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VLA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VLA FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.4Å</td></tr>
-	~~<tr~~ id~~='related'><td class~~="~~sblockLbl~~">~~<b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vlh\|5vlh]]~~, [[~~5vl7~~\|~~5vl7]], [[5vlk\|5vlk]], [[5vll\|5vll]], [[5vlp\|5vlp~~]]</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</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=5vla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vla OCA], [https://pdbe.org/5vla PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vla RCSB], [https://www.ebi.ac.uk/pdbsum/5vla PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vla 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=5vla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vla OCA], [~~http~~://pdbe.org/5vla PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5vla RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5vla PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5vla 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 ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Eigenbrot, C~~]]	+	[[Category: Synthetic construct]]
-	[[Category: ~~Ultsch, M~~]]	+	[[Category: Eigenbrot C]]
-	[[Category: ~~Hydrolase]]~~	+	[[Category: Ultsch M]]
-	~~[[Category: Proprotein convertase]]~~	+
-	~~[[Category: Subtilisin~~]]	+

OCA at 09:36, 4 December 2019

2019-12-04T09:36:36Z

←Older revision		Revision as of 09:36, 4 December 2019
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	==Short PCSK9 delta-P' complex with Fusion2 peptide==		==Short PCSK9 delta-P' complex with Fusion2 peptide==
-	<StructureSection load='5vla' size='340' side='right' caption='[[5vla]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='5vla' size='340' side='right'caption='[[5vla]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5vla]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VLA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VLA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5vla]] is a 2 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=5VLA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VLA FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vlh\|5vlh]], [[5vl7\|5vl7]], [[5vlk\|5vlk]], [[5vll\|5vll]], [[5vlp\|5vlp]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vlh\|5vlh]], [[5vl7\|5vl7]], [[5vlk\|5vlk]], [[5vll\|5vll]], [[5vlp\|5vlp]]</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=5vla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vla OCA], [http://pdbe.org/5vla PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vla RCSB], [http://www.ebi.ac.uk/pdbsum/5vla PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vla 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=5vla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vla OCA], [http://pdbe.org/5vla PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vla RCSB], [http://www.ebi.ac.uk/pdbsum/5vla PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vla ProSAT]</span></td></tr>
	</table>		</table>
Line 25:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Eigenbrot, C]]		[[Category: Eigenbrot, C]]
	[[Category: Ultsch, M]]		[[Category: Ultsch, M]]

OCA at 03:53, 6 September 2017

2017-09-06T03:53:48Z

←Older revision		Revision as of 03:53, 6 September 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5vla is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Short PCSK9 delta-P' complex with Fusion2 peptide==
		+	<StructureSection load='5vla' size='340' side='right' caption='[[5vla]], [[Resolution\|resolution]] 2.40Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5vla]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5VLA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VLA FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vlh\|5vlh]], [[5vl7\|5vl7]], [[5vlk\|5vlk]], [[5vll\|5vll]], [[5vlp\|5vlp]]</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=5vla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vla OCA], [http://pdbe.org/5vla PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vla RCSB], [http://www.ebi.ac.uk/pdbsum/5vla PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vla 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 subtilisin/kexin type 9 (PCSK9) regulates plasma LDL cholesterol (LDL-c) levels by promoting the degradation of liver LDL receptors (LDLRs). Antibodies that inhibit PCSK9 binding to the EGF(A) domain of the LDLR are effective in lowering LDL-c. However, the discovery of small-molecule therapeutics is hampered by difficulty in targeting the relatively flat EGF(A)-binding site on PCSK9. Here we demonstrate that it is possible to target this site, based on the finding that the PCSK9 P' helix displays conformational flexibility. As a consequence, the vacated N-terminal groove of PCSK9, which is adjacent to the EGF(A)-binding site, is in fact accessible to small peptides. In phage-display experiments, the EGF(A)-mimicking peptide Pep2-8 was used as an anchor peptide for the attachment of an extension peptide library directed toward the groove site. Guided by structural information, we further engineered the identified groove-binding peptides into antagonists, which encroach on the EGF(A)-binding site and inhibit LDLR binding.

-	~~Authors: Eigenbrot, C~~., Ultsch, M.	+	Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists.,Zhang Y, Ultsch M, Skelton NJ, Burdick DJ, Beresini MH, Li W, Kong-Beltran M, Peterson A, Quinn J, Chiu C, Wu Y, Shia S, Moran P, Di Lello P, Eigenbrot C, Kirchhofer D Nat Struct Mol Biol. 2017 Aug 21. doi: 10.1038/nsmb.3453. PMID:28825733<ref>PMID:28825733</ref>

-	~~Description: Short PCSK9 delta-P' complex with Fusion2 peptide~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	~~[[Category~~: ~~Ultsch, M]]~~	+	<div class="pdbe-citations 5vla" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Eigenbrot, C]]		[[Category: Eigenbrot, C]]
		+	[[Category: Ultsch, M]]
		+	[[Category: Hydrolase]]
		+	[[Category: Proprotein convertase]]
		+	[[Category: Subtilisin]]

OCA at 13:57, 17 May 2017

2017-05-17T13:57:37Z

←Older revision		Revision as of 13:57, 17 May 2017
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5vla is ON HOLD	+	The entry 5vla is ON HOLD until Paper Publication

	Authors: Eigenbrot, C., Ultsch, M.		Authors: Eigenbrot, C., Ultsch, M.

OCA: Protected "5vla" [edit=sysop:move=sysop]

2017-05-04T11:26:31Z

Protected "5vla" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:26, 4 May 2017

OCA: New page: '''Unreleased structure''' The entry 5vla is ON HOLD Authors: Eigenbrot, C., Ultsch, M. Description: Short PCSK9 delta-P' complex with Fusion2 peptide [[Category: Unreleased Structures...

2017-05-04T11:26:30Z

New page: '''Unreleased structure''' The entry 5vla is ON HOLD Authors: Eigenbrot, C., Ultsch, M. Description: Short PCSK9 delta-P' complex with Fusion2 peptide [[Category: Unreleased Structures...

New page

'''Unreleased structure'''

The entry 5vla is ON HOLD

Authors: Eigenbrot, C., Ultsch, M.

Description: Short PCSK9 delta-P' complex with Fusion2 peptide
[[Category: Unreleased Structures]]
[[Category: Ultsch, M]]
[[Category: Eigenbrot, C]]