Allosteric pathways in the PPARγ-RXRα nuclear receptor complex

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 loops and PPAR 3-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.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 p6FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO2013/08293-7Lefstin, J.A., Yamamoto, K.R., Allosteric effects of DNA on transcriptional regulators (1998) Nature, 392, pp. 885-888Motlagh, H.N., Wrabl, J.O., Li, J., Hilser, V.J., The ensemble nature of allostery (2014) Nature, 508, pp. 331-339Conn, P.J., Christopoulos, A., Lindsley, C.W., Allosteric modulators of gpcrs: A novel approach for the treatment of cns disorders (2009) Nat. Rev. Drug Discovery, 8, pp. 41-54Fidelak, J., Dynamic correlation networks in human peroxisome proliferator-activated receptor-gamma nuclear receptor protein (2010) Eur. 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We would like to thank Prof. Richard Lavery for kindly adapting the Curves + program to handle PDB trajectories. VSB acknowledges supercomputer time from the Natio