6r8l - Revision history

OCA at 12:17, 24 January 2024

OCA — Wed, 24 Jan 2024 12:17:09 GMT

←Older revision		Revision as of 12:17, 24 January 2024
Line 3:		Line 3:
	<StructureSection load='6r8l' size='340' side='right'caption='[[6r8l]], [[Resolution\|resolution]] 1.64Å' scene=''>		<StructureSection load='6r8l' size='340' side='right'caption='[[6r8l]], [[Resolution\|resolution]] 1.64Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6r8l]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8L OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6R8L FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6r8l]] is a 1 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=6R8L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R8L FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JUZ:1-[2-[(2~{R})-2-(2-methylsulfanylphenyl)pyrrolidin-1-yl]-2-oxidanylidene-ethyl]-3-[[(1~{S},9~{S},10~{S})-10-oxidanyl-12-oxa-8-azatricyclo[7.3.1.0^{2,7}]trideca-2(7),3,5-trien-4-yl]methyl]urea'>JUZ</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]] 1.64Å</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JUZ:1-[2-[(2~{R})-2-(2-methylsulfanylphenyl)pyrrolidin-1-yl]-2-oxidanylidene-ethyl]-3-[[(1~{S},9~{S},10~{S})-10-oxidanyl-12-oxa-8-azatricyclo[7.3.1.0^{2,7}]trideca-2(7),3,5-trien-4-yl]methyl]urea'>JUZ</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=6r8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8l OCA], [~~http~~://pdbe.org/6r8l PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6r8l RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6r8l PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8l ProSAT]</span></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=6r8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8l OCA], [https://pdbe.org/6r8l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r8l RCSB], [https://www.ebi.ac.uk/pdbsum/6r8l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8l ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PPIF_HUMAN PPIF_HUMAN]] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probablity of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.<ref>PMID:19228691</ref> <ref>PMID:22726440</ref>	+	[https://www.uniprot.org/uniprot/PPIF_HUMAN PPIF_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probablity of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.<ref>PMID:19228691</ref> <ref>PMID:22726440</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 6r8l" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6r8l" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Cyclophilin 3D structures\|Cyclophilin 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Peptidylprolyl isomerase]]~~	+	[[Category: Graedler U]]
-	[[Category: Graedler, U]]	+
-	~~[[Category: Beta barrel]]~~	+
-	~~[[Category: Cyclophilin]]~~	+
-	~~[[Category: Isomerase]]~~	+
-	~~[[Category: Mitoc]]~~	+
-	~~[[Category: Prolyl cis/trans isomerase~~]]	+

OCA at 06:56, 27 November 2019

OCA — Wed, 27 Nov 2019 06:56:23 GMT

←Older revision		Revision as of 06:56, 27 November 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6r8l is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Human Cyclophilin D in complex with 1-((1S,9S,10S)-10-Hydroxy-12-oxa-8-aza-tricyclo[7.3.1.02,7]trideca-2,4,6-trien-4-ylmethyl)-3- {2-[(R)-2-(2-methylsulfanyl-phenyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-urea==
		+	<StructureSection load='6r8l' size='340' side='right'caption='[[6r8l]], [[Resolution\|resolution]] 1.64Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6r8l]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R8L FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JUZ:1-[2-[(2~{R})-2-(2-methylsulfanylphenyl)pyrrolidin-1-yl]-2-oxidanylidene-ethyl]-3-[[(1~{S},9~{S},10~{S})-10-oxidanyl-12-oxa-8-azatricyclo[7.3.1.0^{2,7}]trideca-2(7),3,5-trien-4-yl]methyl]urea'>JUZ</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </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=6r8l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8l OCA], [http://pdbe.org/6r8l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r8l RCSB], [http://www.ebi.ac.uk/pdbsum/6r8l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8l ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PPIF_HUMAN PPIF_HUMAN]] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probablity of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.<ref>PMID:19228691</ref> <ref>PMID:22726440</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.

-	~~Authors~~:	+	Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.,Gradler U, Schwarz D, Blaesse M, Leuthner B, Johnson TL, Bernard F, Jiang X, Marx A, Gilardone M, Lemoine H, Roche D, Jorand-Lebrun C Bioorg Med Chem Lett. 2019 Dec 1;29(23):126717. doi: 10.1016/j.bmcl.2019.126717. , Epub 2019 Oct 16. PMID:31635932<ref>PMID:31635932</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6r8l" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Peptidylprolyl isomerase]]
		+	[[Category: Graedler, U]]
		+	[[Category: Beta barrel]]
		+	[[Category: Cyclophilin]]
		+	[[Category: Isomerase]]
		+	[[Category: Mitoc]]
		+	[[Category: Prolyl cis/trans isomerase]]

OCA: Protected "6r8l" [edit=sysop:move=sysop]

OCA — Wed, 10 Apr 2019 05:43:41 GMT

Protected "6r8l" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:43, 10 April 2019

OCA: New page: '''Unreleased structure''' The entry 6r8l is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

OCA — Wed, 10 Apr 2019 05:43:40 GMT

New page: '''Unreleased structure''' The entry 6r8l is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6r8l is ON HOLD until Paper Publication

Authors:

Description:
[[Category: Unreleased Structures]]