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

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  • Matteo Masetti
  • Federico Falchi
  • Maurizio Recanatini

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.

Suggested Citation

  • Matteo Masetti & Federico Falchi & Maurizio Recanatini, 2014. "Protein Dynamics of the HIF-2α PAS-B Domain upon Heterodimerization and Ligand Binding," PLOS ONE, Public Library of Science, vol. 9(4), pages 1-13, April.
    • Handle: RePEc:plo:pone00:0094986
    DOI: 10.1371/journal.pone.0094986
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