Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding

Author(s)

Batista, Fernanda A. H. ^[1] ; Trivella, Daniela B. B. ^[1] ; Bernardes, Amanda ^[1] ; Gratieri, Joyce ^[1] ; Oliveira, Paulo S. L. ^[2] ; Figueira, Ana Carolina M. ^[2] ; Webb, Paul ^{[3, 4]} ; Polikarpov, Igor ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Fis Sao Carlos, Sao Paulo - Brazil

^[2] Ctr Nacl Pesquisas Energia & Mat CNPEM ABTLUS Lab, Lab Nacl Biociencias, Sao Paulo - Brazil

^[3] Methodist Hosp Res Inst, Ctr Diabet, Houston, TX - USA

^[4] Methodist Hosp Res Inst, Canc Res Unit, Houston, TX - USA

• Document type: Journal article
• Source: PLoS One; v. 7, n. 5 MAY 11 2012.
• Web of Science Citations: 25

Abstract

Peroxisome proliferator activated receptors (PPARs delta, alpha and gamma) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPAR delta more than 300-fold more tightly than PPAR alpha or PPAR gamma but the structural basis of PPAR delta: GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPAR delta:GW0742 complex. Comparisons of the PPAR delta:GW0742 complex with published structures of PPARs in complex with alpha and gamma selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPAR delta selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPAR alpha and gamma ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPAR delta ligand design. (AU)

• FAPESP's process: 06/00182-8 - Structural biophysics of nuclear receptors and related proteins
• Grantee: Igor Polikarpov
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 09/53853-5 - Acquisition of a high-performance platform for computational analyses applied to the field of medicine
• Grantee: Wilson Araújo da Silva Junior
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 10/17048-8 - Regulation of genic transactivation and transrepression mediated by nuclear receptors
• Grantee: Ana Carolina Migliorini Figueira
• Support Opportunities: Regular Research Grants