title: 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.
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.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Ohashi
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Gamo
authors.affiliation: Department of Biotechnology, Faculty of Life and Environmental Sciences, University of Yamanashi, 4-3-37 Takeda, Yamanashi 400-8510, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Oyama
authors.affiliation: 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.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D045162:Thiazolidinediones / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: PPAR; Partial agonist; Peroxisome proliferator-activated receptor; X-ray