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Mol Endocrinol. 2016 Feb;30(2):173-88. doi: 10.1210/me.2015-1177. Epub 2016 Jan 8.

Structural Analysis on the Pathologic Mutant Glucocorticoid Receptor Ligand-Binding Domains.

Author information

1
Bioinformatics and Computational Biosciences Branch (D.E.H.), Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852; Program in Reproductive and Adult Endocrinology (S.S., T.M., T.K.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Department of Pediatrics (S.S.), Asahikawa Medical University, Asahikawa 078-8510, Japan; Division of Endocrinology, Metabolism and Diabetes (E.C.), First Department of Pediatrics, University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens 11527, Greece; and Department of Experimental Therapeutics (T.K.), Division of Experimental Biology, Sidra Medical and Research Center, Doha, Qatar.

Abstract

Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR.

PMID:
26745667
PMCID:
PMC4792232
DOI:
10.1210/me.2015-1177
[Indexed for MEDLINE]
Free PMC Article

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