Publication Date:
2007-08-19
Description:
The structural mechanisms by which proteins have evolved new functions are known only indirectly. We report x-ray crystal structures of a resurrected ancestral protein-the approximately 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" mutations-substitutions of no immediate consequence, which stabilize specific elements of the protein and allow it to tolerate subsequent function-switching changes-played a major role in determining GR's evolutionary trajectory.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519897/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519897/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ortlund, Eric A -- Bridgham, Jamie T -- Redinbo, Matthew R -- Thornton, Joseph W -- F32-GM074398/GM/NIGMS NIH HHS/ -- R01 GM081592/GM/NIGMS NIH HHS/ -- R01 GM081592-01/GM/NIGMS NIH HHS/ -- R01 GM081592-02/GM/NIGMS NIH HHS/ -- R01-DK622229/DK/NIDDK NIH HHS/ -- R01-GM081592/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2007 Sep 14;317(5844):1544-8. Epub 2007 Aug 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17702911" target="_blank"〉PubMed〈/a〉
Keywords:
Aldosterone/metabolism
;
Amino Acid Sequence
;
Amino Acid Substitution
;
Animals
;
Crystallography, X-Ray
;
Epistasis, Genetic
;
*Evolution, Molecular
;
Humans
;
Hydrocortisone/metabolism
;
Ligands
;
Likelihood Functions
;
Models, Molecular
;
Molecular Sequence Data
;
Mutation
;
Phylogeny
;
Protein Conformation
;
Protein Structure, Secondary
;
Protein Structure, Tertiary
;
Receptors, Glucocorticoid/*chemistry/*genetics/metabolism
;
Receptors, Mineralocorticoid/*chemistry/*genetics/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
