title: Protein dynamics of the HIF-2α 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-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.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Masetti
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Falchi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D014867:Water / Q000737:chemistry; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D008024:Ligands; D014867:Water; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human
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