Protein Dynamics of the HIF-2α PAS-B Domain upon Heterodimerization and Ligand BindingReportar como inadecuado




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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.



Autor: Matteo Masetti , Federico Falchi, Maurizio Recanatini

Fuente: http://plos.srce.hr/



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