6f2l - Revision history

OCA at 06:17, 19 July 2023

OCA — Wed, 19 Jul 2023 06:17:16 GMT

←Older revision		Revision as of 06:17, 19 July 2023
Line 1:		Line 1:

	==Crystal structure of the complex between PPARgamma LBD and the ligand LJ570: structure obtained from crystals of the apo-form soaked for 15 days.==		==Crystal structure of the complex between PPARgamma LBD and the ligand LJ570: structure obtained from crystals of the apo-form soaked for 15 days.==
-	<StructureSection load='6f2l' size='340' side='right' caption='[[6f2l]], [[Resolution\|resolution]] 2.10Å' scene=''>	+	<StructureSection load='6f2l' size='340' side='right'caption='[[6f2l]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6f2l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F2L OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6F2L FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6f2l]] 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=6F2L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F2L FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=AXY:(2S)-3-(BIPHENYL-4-YL)~~-2~~-(BIPHENYL-4-YLOXY)PROPANOIC+ACID'>AXY</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]] 2.1Å</td></tr>
-	<tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat">~~[[4jl4\|4jl4]]~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AXY:(2S)-3-(BIPHENYL-4-YL)-2-(BIPHENYL-4-YLOXY)PROPANOIC+ACID'>AXY</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=6f2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f2l OCA], [~~http~~://pdbe.org/6f2l PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6f2l RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6f2l PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6f2l 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=6f2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f2l OCA], [https://pdbe.org/6f2l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f2l RCSB], [https://www.ebi.ac.uk/pdbsum/6f2l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f2l 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;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating glucose and lipid metabolism. The search for new PPAR ligands with reduced adverse effects with respect to the marketed antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is highly desired. We report the crystal structure and activity of the two enantiomeric forms of a clofibric acid analogue, respectively complexed with the ligand-binding domain (LBD) of PPARgamma, and provide an explanation on a molecular basis for their different potency and efficacy against PPARgamma. The more potent S-enantiomer is a dual PPARalpha/PPARgamma agonist which presents a partial agonism profile against PPARgamma. Docking of the S-enantiomer in the PPARalpha-LBD has been performed to explain its different subtype pharmacological profile. The hypothesis that partial agonists show differential stabilization of helix 3, when compared to full agonists, is also discussed. Moreover, the structure of the complex with the S-enantiomer reveals a new region of the PPARgamma-LBD never sampled before by other ligands.	+

-	~~Crystal structure of the peroxisome~~ proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design.,Montanari R, Saccoccia F, Scotti E, Crestani M, Godio C, Gilardi F, Loiodice F, Fracchiolla G, Laghezza A, Tortorella P, Lavecchia A, Novellino E, Mazza F, Aschi M, Pochetti G J Med Chem. 2008 Dec 25;51(24):7768-~~76. PMID:19053776<ref>PMID:19053776</ref>~~	+	==See Also==
-		+	*[[Peroxisome proliferator-activated receptor 3D structures\|Peroxisome proliferator-activated receptor 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6f2l" style="background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Montanari, M~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Pochetti, G~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Complex with an agonist~~]]	+	[[Category: Montanari M]]
-	[[Category: ~~Nuclear receptor]]~~	+	[[Category: Pochetti G]]
-	~~[[Category: Transcription]]~~	+
-	~~[[Category: Transcription factor~~]]	+

OCA at 08:34, 10 January 2018

OCA — Wed, 10 Jan 2018 08:34:27 GMT

←Older revision		Revision as of 08:34, 10 January 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6f2l is ~~ON HOLD~~	+	==Crystal structure of the complex between PPARgamma LBD and the ligand LJ570: structure obtained from crystals of the apo-form soaked for 15 days.==
		+	<StructureSection load='6f2l' size='340' side='right' caption='[[6f2l]], [[Resolution\|resolution]] 2.10Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6f2l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F2L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F2L FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AXY:(2S)-3-(BIPHENYL-4-YL)-2-(BIPHENYL-4-YLOXY)PROPANOIC+ACID'>AXY</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4jl4\|4jl4]]</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=6f2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f2l OCA], [http://pdbe.org/6f2l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f2l RCSB], [http://www.ebi.ac.uk/pdbsum/6f2l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f2l 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 ==
		+	The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating glucose and lipid metabolism. The search for new PPAR ligands with reduced adverse effects with respect to the marketed antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is highly desired. We report the crystal structure and activity of the two enantiomeric forms of a clofibric acid analogue, respectively complexed with the ligand-binding domain (LBD) of PPARgamma, and provide an explanation on a molecular basis for their different potency and efficacy against PPARgamma. The more potent S-enantiomer is a dual PPARalpha/PPARgamma agonist which presents a partial agonism profile against PPARgamma. Docking of the S-enantiomer in the PPARalpha-LBD has been performed to explain its different subtype pharmacological profile. The hypothesis that partial agonists show differential stabilization of helix 3, when compared to full agonists, is also discussed. Moreover, the structure of the complex with the S-enantiomer reveals a new region of the PPARgamma-LBD never sampled before by other ligands.

-	~~Authors~~: ~~Pochetti, G~~., Montanari, M.	+	Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design.,Montanari R, Saccoccia F, Scotti E, Crestani M, Godio C, Gilardi F, Loiodice F, Fracchiolla G, Laghezza A, Tortorella P, Lavecchia A, Novellino E, Mazza F, Aschi M, Pochetti G J Med Chem. 2008 Dec 25;51(24):7768-76. PMID:19053776<ref>PMID:19053776</ref>

-	~~Description: Crystal structure~~ of the ~~complex between PPARgamma LBD and the ligand LJ570: structure obtained from crystals~~ of ~~the apo-form soaked for 15 days~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
		+	<div class="pdbe-citations 6f2l" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Montanari, M]]		[[Category: Montanari, M]]
	[[Category: Pochetti, G]]		[[Category: Pochetti, G]]
		+	[[Category: Complex with an agonist]]
		+	[[Category: Nuclear receptor]]
		+	[[Category: Transcription]]
		+	[[Category: Transcription factor]]

OCA: Protected "6f2l" [edit=sysop:move=sysop]

OCA — Wed, 06 Dec 2017 06:11:38 GMT

Protected "6f2l" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:11, 6 December 2017

OCA: New page: '''Unreleased structure''' The entry 6f2l is ON HOLD Authors: Pochetti, G., Montanari, M. Description: Crystal structure of the complex between PPARgamma LBD and the ligand LJ570: stru...

OCA — Wed, 06 Dec 2017 06:11:37 GMT

New page: '''Unreleased structure''' The entry 6f2l is ON HOLD Authors: Pochetti, G., Montanari, M. Description: Crystal structure of the complex between PPARgamma LBD and the ligand LJ570: stru...

New page

'''Unreleased structure'''

The entry 6f2l is ON HOLD

Authors: Pochetti, G., Montanari, M.

Description: Crystal structure of the complex between PPARgamma LBD and the ligand LJ570: structure obtained from crystals of the apo-form soaked for 15 days.
[[Category: Unreleased Structures]]
[[Category: Montanari, M]]
[[Category: Pochetti, G]]