An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position

Abstract The natural ligand 17β-estradiol (E2) is so far believed to induce a unique agonist-bound active conformation in the ligand binding domain (LBD) of the estrogen receptors (ERs). Both subtypes, ERα and ERβ, are transcriptionally activated in the presence of E2 with ERβ being somewhat less ac...

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Autores principales:	Paulo C. T. Souza, Larissa C. Textor, Denise C. Melo, Alessandro S. Nascimento, Munir S. Skaf, Igor Polikarpov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7658c3e0f2b849b89a16ce660fd83156
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spelling	oai:doaj.org-article:7658c3e0f2b849b89a16ce660fd831562021-12-02T16:06:43ZAn alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position10.1038/s41598-017-03774-x2045-2322https://doaj.org/article/7658c3e0f2b849b89a16ce660fd831562017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03774-xhttps://doaj.org/toc/2045-2322Abstract The natural ligand 17β-estradiol (E2) is so far believed to induce a unique agonist-bound active conformation in the ligand binding domain (LBD) of the estrogen receptors (ERs). Both subtypes, ERα and ERβ, are transcriptionally activated in the presence of E2 with ERβ being somewhat less active than ERα under similar conditions. The molecular bases for this intriguing behavior are mainly attributed to subtype differences in the amino-terminal domain of these receptors. However, structural details that confer differences in the molecular response of ER LBDs to E2 still remain elusive. In this study, we present a new crystallographic structure of the ERβ LBD bound to E2 in which H12 assumes an alternative conformation that resembles antagonist ERs structures. Structural observations and molecular dynamics simulations jointly provide evidence that alternative ERβ H12 position could correspond to a stable conformation of the receptor under physiological pH conditions. Our findings shed light on the unexpected role of LBD in the lower functional response of ERβ subtype.Paulo C. T. SouzaLarissa C. TextorDenise C. MeloAlessandro S. NascimentoMunir S. SkafIgor PolikarpovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paulo C. T. Souza Larissa C. Textor Denise C. Melo Alessandro S. Nascimento Munir S. Skaf Igor Polikarpov An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position
description	Abstract The natural ligand 17β-estradiol (E2) is so far believed to induce a unique agonist-bound active conformation in the ligand binding domain (LBD) of the estrogen receptors (ERs). Both subtypes, ERα and ERβ, are transcriptionally activated in the presence of E2 with ERβ being somewhat less active than ERα under similar conditions. The molecular bases for this intriguing behavior are mainly attributed to subtype differences in the amino-terminal domain of these receptors. However, structural details that confer differences in the molecular response of ER LBDs to E2 still remain elusive. In this study, we present a new crystallographic structure of the ERβ LBD bound to E2 in which H12 assumes an alternative conformation that resembles antagonist ERs structures. Structural observations and molecular dynamics simulations jointly provide evidence that alternative ERβ H12 position could correspond to a stable conformation of the receptor under physiological pH conditions. Our findings shed light on the unexpected role of LBD in the lower functional response of ERβ subtype.
format	article
author	Paulo C. T. Souza Larissa C. Textor Denise C. Melo Alessandro S. Nascimento Munir S. Skaf Igor Polikarpov
author_facet	Paulo C. T. Souza Larissa C. Textor Denise C. Melo Alessandro S. Nascimento Munir S. Skaf Igor Polikarpov
author_sort	Paulo C. T. Souza
title	An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position
title_short	An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position
title_full	An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position
title_fullStr	An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position
title_full_unstemmed	An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position
title_sort	alternative conformation of erβ bound to estradiol reveals h12 in a stable antagonist position
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7658c3e0f2b849b89a16ce660fd83156
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An alternative conformation of ERβ bound to estradiol reveals H12 in a stable antagonist position

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