Deciphering Modern Glucocorticoid Cross-pharmacology Using Ancestral Corticosteroid Receptors

• Type of Material: Article
• Authors: Jeffrey A. Kohn, Emory University; Kirti Deshpande, Emory University; Eric Ortlund, Emory University
• Language: English
• Date: 2012-05-11
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://www.jbc.org/content/287/20/16267
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 287
• Issue: 20
• Start Page: 16267
• End Page: 16275
• Keywords: Ancestral Gene Resurrection; Molecular Pharmacology; Molecular Evolution; Glucocorticoids; Drug Design; Steroid Hormone Receptor
• Research Categories: Chemistry, Biochemistry; Health Sciences, Oncology

Abstract

Background: Drugs that target steroid receptors are notoriously promiscuous, causing an array of off-target side effects. Results: Reversal of the historical mutation H853R in the mineralocorticoid receptor (MR) fully restores agonist activity by mometasone furoate, an MR antagonist. Conclusion: A single residue outside of the ligand-binding pocket toggles agonism versus antagonism response by MR to synthetic ligands. Significance: Ancestral proteins are ideal tools to elucidate the mechanisms of drug selectivity.