Protein Dynamics of the HIF-2α PAS-B Domain upon Heterodimerization and Ligand Binding

Matteo Masetti, Federico Falchi and Maurizio Recanatini

PLOS ONE, 2014, vol. 9, issue 4, 1-13

Abstract: 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.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0094986

DOI: 10.1371/journal.pone.0094986

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