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The half-maximal responses (EC50s) for skate MR for the mineralocorticoids aldosterone and 11-deoxycorticosterone are 0.07\u2009nM and 0.03\u2009nM, respectively. EC50s for the glucocorticoids cortisol and corticosterone are 1\u2009nM and 0.09\u2009nM, respectively. The physiological mineralocorticoid in ray-finned fish, which do not synthesize aldosterone, is not fully understood because several 3-ketosteroids, including cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone and progesterone are transcriptional activators of fish MR. Further divergence of the MR and GR in terrestrial vertebrates, which synthesize aldosterone, led to emergence of aldosterone as a selective ligand for the MR. Here, we combine sequence analysis of the CR and vertebrate MRs and GRs, analysis of crystal structures of human MR and GR and data on transcriptional activation by 3-ketosteroids of wild-type and mutant MRs and GRs to investigate the evolution of selectivity for 3-ketosteroids by the MR in terrestrial vertebrates and ray-finned fish, as well as the basis for binding of some glucocorticoids by human MR and other vertebrate MRs.<\/jats:p>","DOI":"10.1530\/joe-16-0661","type":"journal-article","created":{"date-parts":[[2017,5,3]],"date-time":"2017-05-03T20:40:22Z","timestamp":1493844022000},"page":"T1-T16","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":88,"title":["30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function"],"prefix":"10.1530","volume":"234","author":[{"given":"Michael E","family":"Baker","sequence":"first","affiliation":[{"name":"1Division of Nephrology-HypertensionDepartment of Medicine, University of California, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinao","family":"Katsu","sequence":"additional","affiliation":[{"name":"2Graduate School of Life ScienceHokkaido University, Sapporo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"2017062017101042000_234.1.T1.1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(88)90136-5"},{"key":"2017062017101042000_234.1.T1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3037703"},{"key":"2017062017101042000_234.1.T1.3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1471-2148-11-14","article-title":"Evolution of ligand specificity in vertebrate corticosteroid receptors","volume":"11","author":"Arterbery","year":"2011","journal-title":"BMC Evolutionary Biology"},{"key":"2017062017101042000_234.1.T1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0303-7207(97)00207-4"},{"key":"2017062017101042000_234.1.T1.5","doi-asserted-by":"publisher","DOI":"10.1210\/en.2003-0843"},{"key":"2017062017101042000_234.1.T1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.07.057"},{"key":"2017062017101042000_234.1.T1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2010.07.013"},{"key":"2017062017101042000_234.1.T1.8","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1471-2148-7-24","article-title":"Structural analysis of the evolution of steroid specificity in the mineralocorticoid and glucocorticoid receptors","volume":"7","author":"Baker","year":"2007","journal-title":"BMC Evolutionary Biology"},{"key":"2017062017101042000_234.1.T1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2013.07.009"},{"key":"2017062017101042000_234.1.T1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2014.10.020"},{"key":"2017062017101042000_234.1.T1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2011.07.015"},{"key":"2017062017101042000_234.1.T1.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504098200"},{"key":"2017062017101042000_234.1.T1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00817-6"},{"key":"2017062017101042000_234.1.T1.14","doi-asserted-by":"publisher","DOI":"10.1210\/en.134.3.1286"},{"key":"2017062017101042000_234.1.T1.15","doi-asserted-by":"crossref","first-page":"e1000191","DOI":"10.1371\/journal.pgen.1000191","article-title":"Evolution of a new function by degenerative mutation in cephalochordate steroid receptors","volume":"4","author":"Bridgham","year":"2008","journal-title":"PLoS Genetics"},{"key":"2017062017101042000_234.1.T1.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.1123348"},{"key":"2017062017101042000_234.1.T1.17","doi-asserted-by":"crossref","unstructured":"Bridgham JT Eick GN Larroux C Deshpande K Harms MJ Gauthier ME Ortlund EA Degnan BM Thornton JW 2010 Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor. 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