6e5a - Revision history

OCA at 06:19, 11 October 2023

OCA — Wed, 11 Oct 2023 06:19:11 GMT

←Older revision		Revision as of 06:19, 11 October 2023
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	<StructureSection load='6e5a' size='340' side='right'caption='[[6e5a]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='6e5a' size='340' side='right'caption='[[6e5a]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6e5a]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E5A OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6E5A FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6e5a]] is a 2 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=6E5A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E5A FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=HV4:(5Z)-5-({4~~-[~~(prop-2-yn-1-yl)oxy~~]~~phenyl}methylidene)-~~2~~-sulfanylidene-1,3-thiazolidin-~~4~~-one'>HV4</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='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=HV4:(5Z)-5-({4-[(prop-2-yn-1-yl)oxy]phenyl}methylidene)-2-sulfanylidene-1,3-thiazolidin-4-one'>HV4</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=6e5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e5a OCA], [~~http~~://pdbe.org/6e5a PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6e5a RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6e5a PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6e5a 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=6e5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e5a OCA], [https://pdbe.org/6e5a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e5a RCSB], [https://www.ebi.ac.uk/pdbsum/6e5a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e5a ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[~~http~~://omim.org/entry/601665 601665]]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[~~http~~://omim.org/entry/604367 604367]]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[~~http~~://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.	+	[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[https://omim.org/entry/601665 601665]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[https://omim.org/entry/604367 604367]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[https://omim.org/entry/137800 137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>	+	[https://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</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: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Bruning~~, J B~~]]	+	[[Category: Bruning JB]]
-	[[Category: Chua~~, B S.K]]~~	+	[[Category: Chua BSK]]
-	~~[[Category: Ligand binding domain]]~~	+
-	~~[[Category: Nuclear receptor]]~~	+
-	~~[[Category: Ppar]]~~	+
-	~~[[Category: Transcription]]~~	+
-	~~[[Category: Transcription factor~~]]	+

OCA at 11:56, 13 March 2019

OCA — Wed, 13 Mar 2019 11:56:31 GMT

←Older revision		Revision as of 11:56, 13 March 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6e5a is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==PPARg in complex with compound 4b==
		+	<StructureSection load='6e5a' size='340' side='right'caption='[[6e5a]], [[Resolution\|resolution]] 2.40Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6e5a]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E5A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E5A FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HV4:(5Z)-5-({4-[(prop-2-yn-1-yl)oxy]phenyl}methylidene)-2-sulfanylidene-1,3-thiazolidin-4-one'>HV4</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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=6e5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e5a OCA], [http://pdbe.org/6e5a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e5a RCSB], [http://www.ebi.ac.uk/pdbsum/6e5a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e5a ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:[http://omim.org/entry/601665 601665]]. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[http://omim.org/entry/604367 604367]]. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[http://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PPARG_HUMAN PPARG_HUMAN]] Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARgamma ligands. Challenging our design with pre-synthetic docking experiments on PPARgamma showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARgamma agonist, potent COX-2 antagonist (nanomolar IC50 values) and moderate 15-LOX inhibitor (micromolar IC50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARgamma nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARgamma X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors.

-	~~Authors~~: Bruning, J.B.~~, Chua, B~~.S.K.	+	Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones.,Elzahhar PA, Alaaeddine R, Ibrahim TM, Nassra R, Ismail A, Chua BSK, Frkic RL, Bruning JB, Wallner N, Knape T, von Knethen A, Labib H, El-Yazbi AF, Belal ASF Eur J Med Chem. 2019 Apr 1;167:562-582. doi: 10.1016/j.ejmech.2019.02.034. Epub, 2019 Feb 13. PMID:30818268<ref>PMID:30818268</ref>

-	~~Description~~: ~~PPARg in complex with compound 4b~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Chua, B.S.K]]	+	<div class="pdbe-citations 6e5a" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Bruning, J.B~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Bruning, J B]]
		+	[[Category: Chua, B S.K]]
		+	[[Category: Ligand binding domain]]
		+	[[Category: Nuclear receptor]]
		+	[[Category: Ppar]]
		+	[[Category: Transcription]]
		+	[[Category: Transcription factor]]

OCA at 04:38, 22 August 2018

OCA — Wed, 22 Aug 2018 04:38:34 GMT

←Older revision		Revision as of 04:38, 22 August 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6e5a is ON HOLD	+	The entry 6e5a is ON HOLD until Paper Publication

	Authors: Bruning, J.B., Chua, B.S.K.		Authors: Bruning, J.B., Chua, B.S.K.
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	Description: PPARg in complex with compound 4b		Description: PPARg in complex with compound 4b
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Bruning, J.B]]
	[[Category: Chua, B.S.K]]		[[Category: Chua, B.S.K]]
		+	[[Category: Bruning, J.B]]

OCA: Protected "6e5a" [edit=sysop:move=sysop]

OCA — Wed, 25 Jul 2018 05:59:47 GMT

Protected "6e5a" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:59, 25 July 2018

OCA: New page: '''Unreleased structure''' The entry 6e5a is ON HOLD Authors: Bruning, J.B., Chua, B.S.K. Description: PPARg in complex with compound 4b Category: Unreleased Structures [[Category:...

OCA — Wed, 25 Jul 2018 05:59:46 GMT

New page: '''Unreleased structure''' The entry 6e5a is ON HOLD Authors: Bruning, J.B., Chua, B.S.K. Description: PPARg in complex with compound 4b Category: Unreleased Structures [[Category:...

New page

'''Unreleased structure'''

The entry 6e5a is ON HOLD

Authors: Bruning, J.B., Chua, B.S.K.

Description: PPARg in complex with compound 4b
[[Category: Unreleased Structures]]
[[Category: Bruning, J.B]]
[[Category: Chua, B.S.K]]