Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.

Hypoxia-Inducible Factor (HIF) transcription factors are heterodimeric proteins involved in the regulation of oxygen homeostatis. Their upregulation has been related to several tumors with a remarkably poor clinical outcome. The recent discovery of a druggable cavity in the HIF-2α PAS-B domain has o...

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Autores principales:	Matteo Masetti, Federico Falchi, Maurizio Recanatini
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/91c95918eb064d58a42fd8e7c301d88c
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spelling	oai:doaj.org-article:91c95918eb064d58a42fd8e7c301d88c2021-11-18T08:23:19ZProtein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.1932-620310.1371/journal.pone.0094986https://doaj.org/article/91c95918eb064d58a42fd8e7c301d88c2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24736273/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Hypoxia-Inducible Factor (HIF) transcription factors are heterodimeric proteins involved in the regulation of oxygen homeostatis. Their upregulation has been related to several tumors with a remarkably poor clinical outcome. The recent discovery of a druggable cavity in the HIF-2α PAS-B domain has opened an unprecedented opportunity for targeting the HIF-2α transcription factor in view of pharmaceutical strategies. Coincidentally, a novel compound able to selectively disrupt the HIF heterodimerization with a submicromolar activity has been reported. In this work, we investigated the molecular mechanisms responsible for the inhibition by comparing the dynamical features of the HIF-2α PAS-B monomer and the HIF-2α PAS-B/HIF-1β PAS-B complex, in the ligand-bound and -unbound states. Plain and biased Molecular Dynamics were used to characterize the differential conformational changes both structurally and energetically.Matteo MasettiFederico FalchiMaurizio RecanatiniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e94986 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matteo Masetti Federico Falchi Maurizio Recanatini Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.
description	Hypoxia-Inducible Factor (HIF) transcription factors are heterodimeric proteins involved in the regulation of oxygen homeostatis. Their upregulation has been related to several tumors with a remarkably poor clinical outcome. The recent discovery of a druggable cavity in the HIF-2α PAS-B domain has opened an unprecedented opportunity for targeting the HIF-2α transcription factor in view of pharmaceutical strategies. Coincidentally, a novel compound able to selectively disrupt the HIF heterodimerization with a submicromolar activity has been reported. In this work, we investigated the molecular mechanisms responsible for the inhibition by comparing the dynamical features of the HIF-2α PAS-B monomer and the HIF-2α PAS-B/HIF-1β PAS-B complex, in the ligand-bound and -unbound states. Plain and biased Molecular Dynamics were used to characterize the differential conformational changes both structurally and energetically.
format	article
author	Matteo Masetti Federico Falchi Maurizio Recanatini
author_facet	Matteo Masetti Federico Falchi Maurizio Recanatini
author_sort	Matteo Masetti
title	Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.
title_short	Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.
title_full	Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.
title_fullStr	Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.
title_full_unstemmed	Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.
title_sort	protein dynamics of the hif-2α pas-b domain upon heterodimerization and ligand binding.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/91c95918eb064d58a42fd8e7c301d88c
work_keys_str_mv	AT matteomasetti proteindynamicsofthehif2apasbdomainuponheterodimerizationandligandbinding AT federicofalchi proteindynamicsofthehif2apasbdomainuponheterodimerizationandligandbinding AT mauriziorecanatini proteindynamicsofthehif2apasbdomainuponheterodimerizationandligandbinding
_version_	1718421873173200896

Protein dynamics of the HIF-2α PAS-B domain upon heterodimerization and ligand binding.

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