title: Allosteric Pathways in the PPARγ-RXRα nuclear receptor complex.
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 Ω-loops and PPARγ-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.
authors.affiliation: Institute of Chemistry, University of Campinas-UNICAMP, Cx. P. 6154, Campinas SP 13084-862, Brazil.
authors.forename: Clarisse G
authors.initials: CG
authors.lastname: Ricci
authors.affiliation: Institute of Chemistry, University of Campinas-UNICAMP, Cx. P. 6154, Campinas SP 13084-862, Brazil.
authors.forename: Rodrigo L
authors.initials: RL
authors.lastname: Silveira
authors.affiliation: Université de Lyon, CNRS, Laboratoire de Chimie, École Normale Supérieure de Lyon, UMR 5182, 46 Allée d'Italie, 69364 Lyon, Cedex 07, France.|Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520-8167, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rivalta
authors.affiliation: Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520-8167, United States.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
authors.affiliation: Institute of Chemistry, University of Campinas-UNICAMP, Cx. P. 6154, Campinas SP 13084-862, Brazil.
authors.forename: Munir S
authors.initials: MS
authors.lastname: Skaf
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D047495:PPAR gamma / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D021281:Quantitative Structure-Activity Relationship; D047490:Retinoid X Receptor alpha / Q000737:chemistry* / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D004247:DNA
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