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==Peroxisome proliferator-activated receptor gamma lignad binding domain in complex with a novel selectively PPAR gamma-modulating ligand VSP-51== | |||
<StructureSection load='5two' size='340' side='right' caption='[[5two]], [[Resolution|resolution]] 1.93Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5two]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TWO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TWO FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7MV:N-BENZYL-1-[(4-CHLORO-3-FLUOROPHENYL)METHYL]-1H-INDOLE-5-CARBOXAMIDE'>7MV</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=5two FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5two OCA], [http://pdbe.org/5two PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5two RCSB], [http://www.ebi.ac.uk/pdbsum/5two PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5two 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 == | |||
Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent "hit" compound, VSP-51, which is a novel selective PPARgamma-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPARgamma with improved insulin sensitivity due to its ability to bind PPARgamma with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPARgamma ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for anti-diabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPARgamma with advantages over current TZD drugs. | |||
Identification of a novel selective PPARgamma ligand with a unique binding mode and improved therapeutic profile in vitro.,Yi W, Shi J, Zhao G, Zhou XE, Suino-Powell K, Melcher K, Xu HE Sci Rep. 2017 Jan 27;7:41487. doi: 10.1038/srep41487. PMID:28128331<ref>PMID:28128331</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5two" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Melcher, K]] | [[Category: Melcher, K]] | ||
[[Category: Shi, J]] | |||
[[Category: Suino-Powell, K]] | |||
[[Category: Xu, H E]] | |||
[[Category: Yi, W]] | [[Category: Yi, W]] | ||
[[Category: Zhao, G]] | [[Category: Zhao, G]] | ||
[[Category: | [[Category: Zhou, X E]] | ||
[[Category: Dna binding protein]] | |||
[[Category: Lignad binding domain]] | |||
[[Category: Peroxisome proliferator-activated receptor gamma]] | |||
[[Category: Selective ppar gamma ligand]] | |||
[[Category: Transcription]] | |||
[[Category: Vsp-51]] | |||
Revision as of 12:28, 10 March 2017
Peroxisome proliferator-activated receptor gamma lignad binding domain in complex with a novel selectively PPAR gamma-modulating ligand VSP-51Peroxisome proliferator-activated receptor gamma lignad binding domain in complex with a novel selectively PPAR gamma-modulating ligand VSP-51
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 PubMedThiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent "hit" compound, VSP-51, which is a novel selective PPARgamma-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPARgamma with improved insulin sensitivity due to its ability to bind PPARgamma with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPARgamma ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for anti-diabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPARgamma with advantages over current TZD drugs. Identification of a novel selective PPARgamma ligand with a unique binding mode and improved therapeutic profile in vitro.,Yi W, Shi J, Zhao G, Zhou XE, Suino-Powell K, Melcher K, Xu HE Sci Rep. 2017 Jan 27;7:41487. doi: 10.1038/srep41487. PMID:28128331[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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