Cryo-EM of human P-glycoprotein reveals an intermediate occluded conformation during active drug transport.

ABSTRACT: P-glycoprotein (Pgp) is an important human multidrug transporter that contributes to pharmacokinetics and multidrug resistance. Despite decades of study, the conformation transition cycle of Pgp undergoing active drug transport is not defined, thus the precise relevance of all available Pgp structures to uninterrupted multidrug transport remains unclear. Here, we use cryo-EM of membrane-embedded human Pgp under continuous turnover conditions to analyze the conformational ensembles of Pgp transporting distinct substrates. These results delineate multiple conformations including inward-facing and closed conformations, highlighting the occluded conformation as a critical intermediate state between transporter closure and substrate release. A combination of structural, functional, and computat

SUBMITTER: Culbertson AT 

PROVIDER: S-EPMC12003890 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature