Peroxisome proliferator-activated receptor gamma (PPARγ) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARγ partial agonists bind to PPARγ LBD in different conformations

Masao Ohashi; Kanae Gamo; Takuji Oyama; Hiroyuki Miyachi

doi:10.1016/j.bmcl.2015.05.025

Peroxisome proliferator-activated receptor gamma (PPARγ) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARγ partial agonists bind to PPARγ LBD in different conformations

Bioorg Med Chem Lett. 2015 Jul 15;25(14):2758-62. doi: 10.1016/j.bmcl.2015.05.025. Epub 2015 May 22.

Authors

Masao Ohashi¹, Kanae Gamo¹, Takuji Oyama², Hiroyuki Miyachi³

Affiliations

¹ Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
² Department of Biotechnology, Faculty of Life and Environmental Sciences, University of Yamanashi, 4-3-37 Takeda, Yamanashi 400-8510, Japan.
³ Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan. Electronic address: miyachi@pharm.okayama-u.ac.jp.

PMID: 26025876
DOI: 10.1016/j.bmcl.2015.05.025

Abstract

In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARγ) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARγ partial agonist 2. Co-crystallization of 3 with the hPPARγ ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARγ LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180° away from that of bound 2. These results support our previous proposal that the hPPARγ LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.

Keywords: PPAR; Partial agonist; Peroxisome proliferator-activated receptor; X-ray.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Crystallography, X-Ray
Dimerization
Humans
Ligands*
Molecular Dynamics Simulation
PPAR gamma / agonists*
PPAR gamma / metabolism
Pioglitazone
Protein Binding
Protein Structure, Tertiary
Thiazolidinediones / chemistry
Thiazolidinediones / metabolism

Substances

Ligands
PPAR gamma
Thiazolidinediones
Pioglitazone