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

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-2? PAS-B domain has opened an unprecedented opportunity for targeting the HIF-2? 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-2? PAS-B monomer and the HIF-2? PAS-B/HIF-1? 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.

SUBMITTER: Masetti M

PROVIDER: S-EPMC3988133 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Masetti Matteo M Falchi Federico F Recanatini Maurizio M

PloS one 20140415 4

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 heterodimeri ...[more]

PMID: 24736273

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