Gating residues govern ligand unbinding kinetics from the buried cavity in HIF-2α PAS-B.

ABSTRACT: While transcription factors have been generally perceived as "undruggable," an exception is the HIF-2 hypoxia-inducible transcription factor, which contains an internal cavity that is sufficiently large to accommodate a range of small-molecules, including the therapeutically used inhibitor belzutifan. Given the relatively long ligand residence times of these small molecules and the lack of any experimentally observed pathway connecting the cavity to solvent, there has been great interest in understanding how these drug ligands exit the buried receptor cavity. Here, we focus on the relevant PAS-B domain of hypoxia-inducible factor 2α (HIF-2α) and examine how one such small molecule (THS-017) exits from the buried cavity within this domain on the seconds-timescale using atomistic simulations

SUBMITTER: Silvestrini ML 

PROVIDER: S-EPMC11516114 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature