Crystal Structure of an Ancient Protein: Evolution by Conformational Epistasis Export

@article{citeulike:1573483, abstract = {The structural mechanisms by which proteins have evolved new functions are known only indirectly. We report x-ray crystal structures of a resurrected ancestral proteinthe \~{}450 million-year-old precursor of vertebrate glucocorticoid (GR) and mineralocorticoid (MR) receptors. Using structural, phylogenetic, and functional analysis, we identify the specific set of historical mutations that recapitulate the evolution of GR's hormone specificity from an MR-like ancestor. These substitutions repositioned crucial residues to create new receptor-ligand and intraprotein contacts. Strong epistatic interactions occur because one substitution changes the conformational position of another site. "Permissive" mutationssubstitutions of no immediate consequence, which stabilize specific elements of the protein and allow it to tolerate subsequent function-switching changesplayed a major role in determining GR's evolutionary trajectory. 10.1126/science.1142819}, author = {Ortlund, Eric A. and Bridgham, Jamie T. and Redinbo, Matthew R. and Thornton, Joseph W.}, citeulike-article-id = {1573483}, citeulike-linkout-0 = {http://dx.doi.org/10.1126/science.1142819}, citeulike-linkout-1 = {http://www.sciencemag.org/cgi/content/abstract/317/5844/1544}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17702911}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17702911}, doi = {10.1126/science.1142819}, journal = {Science}, keywords = {devin\_presented, eisen\_journal\_club, in-depth, round\_robin}, month = {August}, pages = {1142819+}, posted-at = {2007-09-16 01:01:08}, priority = {0}, title = {Crystal Structure of an Ancient Protein: Evolution by Conformational Epistasis}, url = {http://dx.doi.org/10.1126/science.1142819}, year = {2007} }

TY - JOUR ID - citeulike:1573483 L3 - citeulike-article-id:1573483 N2 - The structural mechanisms by which proteins have evolved new functions are known only indirectly. We report x-ray crystal structures of a resurrected ancestral proteinthe ~450 million-year-old precursor of vertebrate glucocorticoid (GR) and mineralocorticoid (MR) receptors. Using structural, phylogenetic, and functional analysis, we identify the specific set of historical mutations that recapitulate the evolution of GR's hormone specificity from an MR-like ancestor. These substitutions repositioned crucial residues to create new receptor-ligand and intraprotein contacts. Strong epistatic interactions occur because one substitution changes the conformational position of another site. "Permissive" mutationssubstitutions of no immediate consequence, which stabilize specific elements of the protein and allow it to tolerate subsequent function-switching changesplayed a major role in determining GR's evolutionary trajectory. 10.1126/science.1142819 JF - Science TI - Crystal Structure of an Ancient Protein: Evolution by Conformational Epistasis SP - 1142819 KW - devin_presented KW - eisen_journal_club KW - in-depth KW - round_robin AU - Ortlund, Eric AU - Bridgham, Jamie AU - Redinbo, Matthew AU - Thornton, Joseph PY - 2007/08/16/ UR - http://dx.doi.org/10.1126/science.1142819 ER -