Structural determinants of allosteric ligand activation in RXR heterodimers. Export

@article{citeulike:342481, abstract = {Allosteric communication underlies ligand-dependent transcriptional responses mediated by nuclear receptors. While studies have elucidated many of the components involved in this process, the energetic architecture within the receptor protein that mediates allostery remains unknown. Using a sequence-based method designed to detect coevolution of amino acids in a protein, termed the statistical coupling analysis (SCA), we identify a network of energetically coupled residues that link the functional surfaces of nuclear receptor ligand binding domains. Functional analysis of these predicted residues demonstrates their participation in an allosteric network that governs the ability of heterodimeric receptors to activate transcription in response to ligand binding by either partner. Interestingly, mutation of a single network residue can discriminate between receptor activation by endocrine, dietary, and synthetic agonists. These results reveal a structural network required for RXR heterodimer allosteric communication and suggest that the specificity of ligand response and permissivity coevolved to enable signal discrimination.}, address = {Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.}, author = {Shulman, A. I. and Larson, C. and Mangelsdorf, D. J. and Ranganathan, R.}, citeulike-article-id = {342481}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/15016376}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=15016376}, day = {6}, issn = {0092-8674}, journal = {Cell}, keywords = {allostery, evolution, statistical\_coupling}, month = {February}, number = {3}, pages = {417--429}, posted-at = {2006-03-09 14:52:03}, priority = {2}, title = {Structural determinants of allosteric ligand activation in RXR heterodimers.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/15016376}, volume = {116}, year = {2004} }

TY - JOUR ID - citeulike:342481 L3 - citeulike-article-id:342481 N2 - Allosteric communication underlies ligand-dependent transcriptional responses mediated by nuclear receptors. While studies have elucidated many of the components involved in this process, the energetic architecture within the receptor protein that mediates allostery remains unknown. Using a sequence-based method designed to detect coevolution of amino acids in a protein, termed the statistical coupling analysis (SCA), we identify a network of energetically coupled residues that link the functional surfaces of nuclear receptor ligand binding domains. Functional analysis of these predicted residues demonstrates their participation in an allosteric network that governs the ability of heterodimeric receptors to activate transcription in response to ligand binding by either partner. Interestingly, mutation of a single network residue can discriminate between receptor activation by endocrine, dietary, and synthetic agonists. These results reveal a structural network required for RXR heterodimer allosteric communication and suggest that the specificity of ligand response and permissivity coevolved to enable signal discrimination. IS - 3 JF - Cell SN - 0092-8674 AD - Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. EP - 429 TI - Structural determinants of allosteric ligand activation in RXR heterodimers. VL - 116 SP - 417 KW - allostery KW - evolution KW - statistical_coupling AU - Shulman, AI AU - Larson, C AU - Mangelsdorf, DJ AU - Ranganathan, R PY - 2004/02/06/ UR - http://view.ncbi.nlm.nih.gov/pubmed/15016376 ER -