6y3u: Difference between revisions
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==Crystal structure of PPARgamma in complex with compound (R)-16== | ==Crystal structure of PPARgamma in complex with compound (R)-16== | ||
<StructureSection load='6y3u' size='340' side='right'caption='[[6y3u]]' scene=''> | <StructureSection load='6y3u' size='340' side='right'caption='[[6y3u]], [[Resolution|resolution]] 2.62Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y3U OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y3U FirstGlance]. <br> | <table><tr><td colspan='2'>[[6y3u]] is a 1 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=6Y3U OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y3U FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y3u OCA], [http://pdbe.org/6y3u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y3u RCSB], [http://www.ebi.ac.uk/pdbsum/6y3u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y3u ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLQ:(2~{R})-2-[[6-[(2,4-dichlorophenyl)sulfonylamino]-1,3-benzothiazol-2-yl]sulfanyl]octanoic+acid'>MLQ</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPARG, NR1C3 ([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://proteopedia.org/fgij/fg.htm?mol=6y3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y3u OCA], [http://pdbe.org/6y3u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y3u RCSB], [http://www.ebi.ac.uk/pdbsum/6y3u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y3u ProSAT]</span></td></tr> | |||
</table> | </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 nuclear peroxisome proliferator-activated receptor gamma has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARgamma modulation are required. Here, we report the discovery and profiling of a new PPARgamma modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARgamma ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARgamma activation with a high eudysmic ratio. The new PPARgamma modulator revealed outstanding selectivity over the PPARalpha and PPARdelta subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists. | |||
A Selective Modulator of Peroxisome Proliferator-Activated Receptor gamma with an Unprecedented Binding Mode.,Hanke T, Cheung SY, Kilu W, Heering J, Ni X, Planz V, Schierle S, Faudone G, Friedrich M, Wanior M, Werz O, Windbergs M, Proschak E, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Merk D J Med Chem. 2020 Apr 20. doi: 10.1021/acs.jmedchem.9b01786. PMID:32267688<ref>PMID:32267688</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6y3u" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Arrowsmith | [[Category: Arrowsmith, C H]] | ||
[[Category: Bountra C]] | [[Category: Bountra, C]] | ||
[[Category: Chaikuad A]] | [[Category: Chaikuad, A]] | ||
[[Category: Edwards | [[Category: Edwards, A M]] | ||
[[Category: Hanke T]] | [[Category: Hanke, T]] | ||
[[Category: Knapp S]] | [[Category: Knapp, S]] | ||
[[Category: Merk D]] | [[Category: Merk, D]] | ||
[[Category: Structural genomic]] | |||
[[Category: Inhibitor]] | |||
[[Category: Nuclear receptor]] | |||
[[Category: Sgc]] | |||
[[Category: Steroid hormone receptor]] | |||
[[Category: Transcription]] | |||
Revision as of 10:17, 29 April 2020
Crystal structure of PPARgamma in complex with compound (R)-16Crystal structure of PPARgamma in complex with compound (R)-16
Structural highlights
Disease[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: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.[1] Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM: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.[2] [3] Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM: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[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.[4] [5] [6] Publication Abstract from PubMedThe nuclear peroxisome proliferator-activated receptor gamma has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARgamma modulation are required. Here, we report the discovery and profiling of a new PPARgamma modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARgamma ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARgamma activation with a high eudysmic ratio. The new PPARgamma modulator revealed outstanding selectivity over the PPARalpha and PPARdelta subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists. A Selective Modulator of Peroxisome Proliferator-Activated Receptor gamma with an Unprecedented Binding Mode.,Hanke T, Cheung SY, Kilu W, Heering J, Ni X, Planz V, Schierle S, Faudone G, Friedrich M, Wanior M, Werz O, Windbergs M, Proschak E, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Merk D J Med Chem. 2020 Apr 20. doi: 10.1021/acs.jmedchem.9b01786. PMID:32267688[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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