6u3i - Revision history

OCA at 07:43, 11 October 2023

OCA — Wed, 11 Oct 2023 07:43:32 GMT

←Older revision		Revision as of 07:43, 11 October 2023
Line 3:		Line 3:
	<StructureSection load='6u3i' size='340' side='right'caption='[[6u3i]], [[Resolution\|resolution]] 2.90Å' scene=''>		<StructureSection load='6u3i' size='340' side='right'caption='[[6u3i]], [[Resolution\|resolution]] 2.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6u3i]] is a 4 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~] and [~~http~~://en.wikipedia.org/wiki/~~Lk3_transgenic_mice Lk3 transgenic mice~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U3I OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6U3I FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6u3i]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U3I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U3I 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]] 2.9Å</td></tr>
-	<tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=HRG:L-HOMOARGININE'>HRG</scene>, <scene name='pdbligand=PQG:'>PQG</scene>~~</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>, <scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=HRG:L-HOMOARGININE'>HRG</scene>, <scene name='pdbligand=PQG:cis-1-amino-4-phenylcyclohexane-1-carboxylic+acid'>PQG</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vlp\|5vlp]]</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=6u3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u3i OCA], [https://pdbe.org/6u3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u3i RCSB], [https://www.ebi.ac.uk/pdbsum/6u3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u3i ProSAT]</span></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=6u3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u3i OCA], [~~http~~://pdbe.org/6u3i PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6u3i RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6u3i PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6u3i 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 23:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 6u3i" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6u3i" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[PCSK9\|PCSK9]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Lk3 transgenic mice~~]]	+	[[Category: Mus musculus]]
-	[[Category: Kirchhofer, D]]	+	[[Category: Kirchhofer D]]
-	[[Category: Ultsch~~, M H]]~~	+	[[Category: Ultsch MH]]
-	~~[[Category: Complex]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor-immune system complex]]~~	+
-	~~[[Category: Inhibitor~~]]	+

OCA at 07:19, 4 March 2020

OCA — Wed, 04 Mar 2020 07:19:45 GMT

←Older revision		Revision as of 07:19, 4 March 2020
Line 3:		Line 3:
	<StructureSection load='6u3i' size='340' side='right'caption='[[6u3i]], [[Resolution\|resolution]] 2.90Å' scene=''>		<StructureSection load='6u3i' size='340' side='right'caption='[[6u3i]], [[Resolution\|resolution]] 2.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6u3i]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U3I FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6u3i]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U3I 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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=HRG:L-HOMOARGININE'>HRG</scene>, <scene name='pdbligand=PQG:'>PQG</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=HRG:L-HOMOARGININE'>HRG</scene>, <scene name='pdbligand=PQG:'>PQG</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vlp\|5vlp]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[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=6u3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u3i OCA], [http://pdbe.org/6u3i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u3i RCSB], [http://www.ebi.ac.uk/pdbsum/6u3i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u3i 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=6u3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u3i OCA], [http://pdbe.org/6u3i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u3i RCSB], [http://www.ebi.ac.uk/pdbsum/6u3i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u3i ProSAT]</span></td></tr>
	</table>		</table>
Line 26:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
		+	[[Category: Lk3 transgenic mice]]
	[[Category: Kirchhofer, D]]		[[Category: Kirchhofer, D]]
	[[Category: Ultsch, M H]]		[[Category: Ultsch, M H]]

OCA at 08:12, 5 February 2020

OCA — Wed, 05 Feb 2020 08:12:07 GMT

←Older revision		Revision as of 08:12, 5 February 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6u3i is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Design of organo-peptides as bipartite PCSK9 antagonists==
		+	<StructureSection load='6u3i' size='340' side='right'caption='[[6u3i]], [[Resolution\|resolution]] 2.90Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6u3i]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U3I 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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=HRG:L-HOMOARGININE'>HRG</scene>, <scene name='pdbligand=PQG:'>PQG</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[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=6u3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u3i OCA], [http://pdbe.org/6u3i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u3i RCSB], [http://www.ebi.ac.uk/pdbsum/6u3i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u3i 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 9 (PCSK9) has become an important therapeutic target for lipid lowering, since it regulates low-density lipoprotein cholesterol (LDL-c) levels by binding to liver LDL receptors (LDLR) and effecting their intracellular degradation. However, the development of small molecule inhibitors is hampered by the lack of attractive PCSK9 target sites. We recently discovered helical peptides that are able to bind to a cryptic groove site on PCSK9, which is situated in proximity to the main LDLR binding site. Here, we designed potent bipartite PCSK9 inhibitors by appending organic moieties to a helical groove-binding peptide to reach a hydrophobic pocket in the proximal LDLR binding region. The ultimately designed 1-amino-4-phenylcyclohexane-1-carbonyl extension improved the peptide affinity by >100-fold, yielding organo-peptide antagonists that potently inhibited PCSK9 binding to LDLR and preserved cellular LDLR. These new bipartite antagonists have reduced mass and improved potency compared to the first-generation peptide antagonists, further validating the PCSK9 groove as a viable therapeutic target site.

-	~~Authors: Ultsch~~, M.H., ~~Kirchhofer~~, D.	+	Design of Organo-Peptides As Bipartite PCSK9 Antagonists.,Burdick DJ, Skelton NJ, Ultsch M, Beresini MH, Eigenbrot C, Li W, Zhang Y, Nguyen H, Kong-Beltran M, Quinn JG, Kirchhofer D ACS Chem Biol. 2020 Jan 30. doi: 10.1021/acschembio.9b00899. PMID:31962046<ref>PMID:31962046</ref>

-	~~Description: Design~~ of ~~organo-peptides as bipartite PCSK9 antagonists~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	[[Category: ~~Ultsch, M.H~~]]	+	<div class="pdbe-citations 6u3i" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Kirchhofer, D]]		[[Category: Kirchhofer, D]]
		+	[[Category: Ultsch, M H]]
		+	[[Category: Complex]]
		+	[[Category: Hydrolase-hydrolase inhibitor-immune system complex]]
		+	[[Category: Inhibitor]]

OCA at 08:09, 2 October 2019

OCA — Wed, 02 Oct 2019 08:09:01 GMT

←Older revision		Revision as of 08:09, 2 October 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6u3i is ON HOLD	+	The entry 6u3i is ON HOLD until Paper Publication

	Authors: Ultsch, M.H., Kirchhofer, D.		Authors: Ultsch, M.H., Kirchhofer, D.

OCA: Protected "6u3i" [edit=sysop:move=sysop]

OCA — Wed, 28 Aug 2019 14:06:36 GMT

Protected "6u3i" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:06, 28 August 2019

OCA: New page: '''Unreleased structure''' The entry 6u3i is ON HOLD Authors: Ultsch, M.H., Kirchhofer, D. Description: Design of organo-peptides as bipartite PCSK9 antagonists [[Category: Unreleased ...

OCA — Wed, 28 Aug 2019 14:06:35 GMT

New page: '''Unreleased structure''' The entry 6u3i is ON HOLD Authors: Ultsch, M.H., Kirchhofer, D. Description: Design of organo-peptides as bipartite PCSK9 antagonists [[Category: Unreleased ...

New page

'''Unreleased structure'''

The entry 6u3i is ON HOLD

Authors: Ultsch, M.H., Kirchhofer, D.

Description: Design of organo-peptides as bipartite PCSK9 antagonists
[[Category: Unreleased Structures]]
[[Category: Ultsch, M.H]]
[[Category: Kirchhofer, D]]