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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aryl Hydrocarbon Receptor Nuclear Translocator / chemistry
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
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Basic Helix-Loop-Helix Transcription Factors / chemistry*
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Humans
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Ligands
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Molecular Docking Simulation
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Molecular Dynamics Simulation*
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Protein Binding
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Protein Conformation
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Protein Interaction Domains and Motifs*
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Protein Multimerization*
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Protein Stability
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Water / chemistry
Substances
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ARNT protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Ligands
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Water
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Aryl Hydrocarbon Receptor Nuclear Translocator
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endothelial PAS domain-containing protein 1
Grants and funding
The authors acknowledge the financial support of Alma Mater Studiorum - University of Bologna. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.