Glucocorticoid Resistance Conferring Mutation in the C-terminus of GR Alters the Receptor Conformational Dynamics

Overview

Journal Sci Rep

Specialty Science

Date 2021 Jun 16

PMID 34131228

Citations 3

Authors

Anna Kaziales

Florian Ruhrnossl

Klaus Richter

Affiliations

Soon will be listed here.

Abstract

The glucocorticoid receptor is a key regulator of essential physiological processes, which under the control of the Hsp90 chaperone machinery, binds to steroid hormones and steroid-like molecules and in a rather complicated and elusive response, regulates a set of glucocorticoid responsive genes. We here examine a human glucocorticoid receptor variant, harboring a point mutation in the last C-terminal residues, L773P, that was associated to Primary Generalized Glucocorticoid Resistance, a condition originating from decreased affinity to hormone, impairing one or multiple aspects of GR action. Using in vitro and in silico methods, we assign the conformational consequences of this mutation to particular GR elements and report on the altered receptor properties regarding its binding to dexamethasone, a NCOA-2 coactivator-derived peptide, DNA, and importantly, its interaction with the chaperone machinery of Hsp90.

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