Conformational dynamics of androgen receptors bound to agonists and antagonists

Abstract The androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic ef...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hyo Jin Gim, Jiyong Park, Michael E. Jung, K. N. Houk
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f6449e9ba37c4b65b086c967080fbebc
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f6449e9ba37c4b65b086c967080fbebc
record_format	dspace
spelling	oai:doaj.org-article:f6449e9ba37c4b65b086c967080fbebc2021-12-02T16:35:31ZConformational dynamics of androgen receptors bound to agonists and antagonists10.1038/s41598-021-94707-22045-2322https://doaj.org/article/f6449e9ba37c4b65b086c967080fbebc2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94707-2https://doaj.org/toc/2045-2322Abstract The androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic efficacy remains unclear, due to the lack of detailed structural information of the AR bound to the antagonists. We have performed accelerated molecular dynamics (aMD) simulations of LBDs bound to a set of ligands including a natural substrate (dihydrotestosterone), an agonist (RU59063) and three antagonists (bicalutamide, enzalutamide and apalutamide) as well as in the absence of ligand (apo). We show that the binding of AR antagonists at the substrate binding pocket alter the dynamic fluctuations of H12, thereby disrupting the structural integrity of the agonistic conformation of AR. Two antagonists, enzalutamide and apalutamide, induce considerable structural changes to the agonist conformation of LBD, when bound close to H12 of AR LBD. When the antagonists bind to the pocket with different orientations having close contact with H11, no significant conformational changes were observed, suggesting the AR remains in the functionally activated (agonistic) state. The simulations on a drug resistance mutant F876L bound to enzalutamide demonstrated that the mutation stabilizes the agonistic conformation of AR LBD, which compromises the efficacy of the antagonists. Principal component analysis (PCA) of the structural fluctuations shows that the binding of enzalutamide and apalutamide induce conformational fluctuations in the AR, which are markedly different from those caused by the agonist as well as another antagonist, bicalutamide. These fluctuations could only be observed with the use of aMD.Hyo Jin GimJiyong ParkMichael E. JungK. N. HoukNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hyo Jin Gim Jiyong Park Michael E. Jung K. N. Houk Conformational dynamics of androgen receptors bound to agonists and antagonists
description	Abstract The androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic efficacy remains unclear, due to the lack of detailed structural information of the AR bound to the antagonists. We have performed accelerated molecular dynamics (aMD) simulations of LBDs bound to a set of ligands including a natural substrate (dihydrotestosterone), an agonist (RU59063) and three antagonists (bicalutamide, enzalutamide and apalutamide) as well as in the absence of ligand (apo). We show that the binding of AR antagonists at the substrate binding pocket alter the dynamic fluctuations of H12, thereby disrupting the structural integrity of the agonistic conformation of AR. Two antagonists, enzalutamide and apalutamide, induce considerable structural changes to the agonist conformation of LBD, when bound close to H12 of AR LBD. When the antagonists bind to the pocket with different orientations having close contact with H11, no significant conformational changes were observed, suggesting the AR remains in the functionally activated (agonistic) state. The simulations on a drug resistance mutant F876L bound to enzalutamide demonstrated that the mutation stabilizes the agonistic conformation of AR LBD, which compromises the efficacy of the antagonists. Principal component analysis (PCA) of the structural fluctuations shows that the binding of enzalutamide and apalutamide induce conformational fluctuations in the AR, which are markedly different from those caused by the agonist as well as another antagonist, bicalutamide. These fluctuations could only be observed with the use of aMD.
format	article
author	Hyo Jin Gim Jiyong Park Michael E. Jung K. N. Houk
author_facet	Hyo Jin Gim Jiyong Park Michael E. Jung K. N. Houk
author_sort	Hyo Jin Gim
title	Conformational dynamics of androgen receptors bound to agonists and antagonists
title_short	Conformational dynamics of androgen receptors bound to agonists and antagonists
title_full	Conformational dynamics of androgen receptors bound to agonists and antagonists
title_fullStr	Conformational dynamics of androgen receptors bound to agonists and antagonists
title_full_unstemmed	Conformational dynamics of androgen receptors bound to agonists and antagonists
title_sort	conformational dynamics of androgen receptors bound to agonists and antagonists
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f6449e9ba37c4b65b086c967080fbebc
work_keys_str_mv	AT hyojingim conformationaldynamicsofandrogenreceptorsboundtoagonistsandantagonists AT jiyongpark conformationaldynamicsofandrogenreceptorsboundtoagonistsandantagonists AT michaelejung conformationaldynamicsofandrogenreceptorsboundtoagonistsandantagonists AT knhouk conformationaldynamicsofandrogenreceptorsboundtoagonistsandantagonists
_version_	1718383729537187840

Conformational dynamics of androgen receptors bound to agonists and antagonists

Ejemplares similares