Allosteric Pathways in the PPAR gamma-RXR alpha nuclear receptor complex

Author(s)

Ricci, Clarisse G. ^[1] ; Silveira, Rodrigo L. ^[1] ; Rivalta, Ivan ^{[2, 3]} ; Batista, Victor S. ^[3] ; Skaf, Munir S. ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Chem, Cx P 6154, BR-13084862 Campinas, SP - Brazil

^[2] Univ Lyon, Ecole Normale Super Lyon, CNRS, Lab Chim, UMR 5182, 46 Allee Italie, F-69364 Lyon 07 - France

^[3] Yale Univ, Dept Chem, POB 208107, New Haven, CT 06520 - USA

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 6, JAN 29 2016.
• Web of Science Citations: 16

Abstract

Understanding the nature of allostery in DNA-nuclear receptor (NR) complexes is of fundamental importance for drug development since NRs regulate the transcription of a myriad of genes in humans and other metazoans. Here, we investigate allostery in the peroxisome proliferator-activated/retinoid X receptor heterodimer. This important NR complex is a target for antidiabetic drugs since it binds to DNA and functions as a transcription factor essential for insulin sensitization and lipid metabolism. We find evidence of interdependent motions of Omega-loops and PPAR gamma-DNA binding domain with contacts susceptible to conformational changes and mutations, critical for regulating transcriptional functions in response to sequence-dependent DNA dynamics. Statistical network analysis of the correlated motions, observed in molecular dynamics simulations, shows preferential allosteric pathways with convergence centers comprised of polar amino acid residues. These findings are particularly relevant for the design of allosteric modulators of ligand-dependent transcription factors. (AU)

• FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
• Grantee: Munir Salomao Skaf
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC