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

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 co

SUBMITTER: Hurt DE 

PROVIDER: S-EPMC4792232 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature