5tto
From Proteopedia
(Difference between revisions)
m (Protected "5tto" [edit=sysop:move=sysop]) |
|||
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==X-ray crystal structure of PPARgamma in complex with SR1643== | |
| + | <StructureSection load='5tto' size='340' side='right' caption='[[5tto]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5tto]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TTO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TTO FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7KK:4-BROMO-N-{3,5-DICHLORO-4-[(QUINOLIN-3-YL)OXY]PHENYL}-2,5-DIFLUOROBENZENE-1-SULFONAMIDE'>7KK</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=5tto FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tto OCA], [http://pdbe.org/5tto PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tto RCSB], [http://www.ebi.ac.uk/pdbsum/5tto PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tto 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 == | ||
| + | Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARgamma is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARgamma with robust antidiabetic properties, which are confounded with significant side effects. Partial agonists of PPARgamma, such as INT131 (1), have displayed similar insulin-sensitizing efficacy as TZDs, but lack many side effects. To probe the structure-activity relationship (SAR) of the scaffold 1, we synthesized 14 analogs of compound 1 which revealed compounds with higher transcriptional potency for PPARgamma and identification of moieties of the scaffold 1 key to high transcriptional potency. The sulfonamide linker is critical to activity, substitutions at position 4 of the benzene ring A were associated with higher transcriptional activity, substitutions at position 2 aided in tighter packing and activity, and the ring type and size of ring A affected the degree of activity. | ||
| - | + | Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPARgamma-Targeted Antidiabetics.,Frkic RL, He Y, Rodriguez BB, Chang MR, Kuruvilla D, Ciesla A, Abell AD, Kamenecka TM, Griffin PR, Bruning JB J Med Chem. 2017 May 22. doi: 10.1021/acs.jmedchem.6b01727. PMID:28485590<ref>PMID:28485590</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5tto" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Abell, A]] | ||
| + | [[Category: Bruning, J B]] | ||
| + | [[Category: Frkic, R L]] | ||
| + | [[Category: Griffin, P]] | ||
| + | [[Category: Kamenecka, T]] | ||
| + | [[Category: Nuclear receptor]] | ||
| + | [[Category: Transcription]] | ||
Revision as of 13:34, 24 May 2017
X-ray crystal structure of PPARgamma in complex with SR1643
| |||||||||||
