5TWO

Peroxisome proliferator-activated receptor gamma ligand binding domain in complex with a novel selectively PPAR gamma-modulating ligand VSP-51

Summary for 5TWO

• Entry DOI: 10.2210/pdb5two/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, PRO-SER-LEU-LEU-LYS-LYS-LEU-LEU-LEU-ALA-PRO, N-benzyl-1-[(4-chloro-3-fluorophenyl)methyl]-1H-indole-5-carboxamide, ... (4 entities in total)
• Functional Keywords: peroxisome proliferator-activated receptor gamma, lignad binding domain, selective ppar gamma ligand, vsp-51, dna binding protein, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 33081.92

Authors

Yi, W.,Shi, J.,Zhao, G.,Zhou, X.E.,Suino-Powell, K.,Melcher, K.,Xu, H.E. (deposition date: 2016-11-14, release date: 2017-02-08, Last modification date: 2023-10-04)

Primary citation

Yi, W.,Shi, J.,Zhao, G.,Zhou, X.E.,Suino-Powell, K.,Melcher, K.,Xu, H.E.
Identification of a novel selective PPAR gamma ligand with a unique binding mode and improved therapeutic profile in vitro.
Sci Rep, 7:41487-41487, 2017

PubMed Abstract: Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), 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 PPARγ-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 PPARγ with improved insulin sensitivity due to its ability to bind PPARγ with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPARγ 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 PPARγ with advantages over current TZD drugs.

PubMed: 28128331
DOI: 10.1038/srep41487

Experimental method

X-RAY DIFFRACTION (1.927 Å)