Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics

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...

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Autores principales:	Anna Kaziales, Florian Rührnößl, Klaus Richter
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8c9e6a950a04427ab5b02f857827df8d
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spelling	oai:doaj.org-article:8c9e6a950a04427ab5b02f857827df8d2021-12-02T17:41:33ZGlucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics10.1038/s41598-021-92039-92045-2322https://doaj.org/article/8c9e6a950a04427ab5b02f857827df8d2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92039-9https://doaj.org/toc/2045-2322Abstract 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.Anna KazialesFlorian RührnößlKlaus RichterNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna Kaziales Florian Rührnößl Klaus Richter Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics
description	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.
format	article
author	Anna Kaziales Florian Rührnößl Klaus Richter
author_facet	Anna Kaziales Florian Rührnößl Klaus Richter
author_sort	Anna Kaziales
title	Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics
title_short	Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics
title_full	Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics
title_fullStr	Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics
title_full_unstemmed	Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics
title_sort	glucocorticoid resistance conferring mutation in the c-terminus of gr alters the receptor conformational dynamics
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8c9e6a950a04427ab5b02f857827df8d
work_keys_str_mv	AT annakaziales glucocorticoidresistanceconferringmutationinthecterminusofgraltersthereceptorconformationaldynamics AT florianruhrnoßl glucocorticoidresistanceconferringmutationinthecterminusofgraltersthereceptorconformationaldynamics AT klausrichter glucocorticoidresistanceconferringmutationinthecterminusofgraltersthereceptorconformationaldynamics
_version_	1718379656315404288

Glucocorticoid resistance conferring mutation in the C-terminus of GR alters the receptor conformational dynamics

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