Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma

Author(s)

dos Santos, Jademilson Celestino ^[1] ; Bernardes, Amanda ^[1] ; Giampietro, Letizia ^[2] ; Ammazzalorso, Alessandra ^[2] ; De Filippis, Barbara ^[2] ; Amoroso, Rosa ^[2] ; Polikarpov, Igor ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, Grp Biotecnol Mol, BR-13566590 Sao Carlos, SP - Brazil

^[2] Univ G DAnnunzio, Dipartimento Farm, I-66100 Chieti - Italy

• Document type: Journal article
• Source: Journal of Structural Biology; v. 191, n. 3, p. 332-340, SEP 2015.
• Web of Science Citations: 16

Abstract

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPAR gamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPAR alpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPAR alpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPAR alpha and PPAR gamma receptors. GL479 was previously reported as a partial agonist of PPAR gamma and a full agonist of PPAR alpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPAR alpha and PPAR gamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPAR alpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPAR gamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPAR alpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia. (C) 2015 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 09/14333-6 - Structural characterization of the peroxisome proliferator-activated receptors (PPARs) types alpha and gamma complexes and its agonists
• Grantee: Jademilson Celestino dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 08/56255-9 - Structure and function of enzymes and auxiliary proteins from Trichoderma, active in cell-wall hydrolysis
• Grantee: Igor Polikarpov
• Support Opportunities: Program for Research on Bioenergy (BIOEN) - Thematic Grants