Drug-bound outward-facing conformation of a heterodimeric ABC exporter suggests a putative mechanism of drug translocation.

ABSTRACT: Multidrug transport by ATP binding cassette (ABC) exporters entails a mechanism to modulate drug affinity across the transport cycle. Here, we combine cryo-EM and molecular dynamics (MD) simulations to illuminate a lipid-competition mechanism to drive substrate translocation by ABC exporters. We determine cryo-EM structures of the ABC transporter BmrCD in drug-loaded inward-facing (IF) and outward-facing (OF) conformations in lipid nanodiscs to reveal the structural basis of alternating access, details of drug-transporter interactions, and the scale of drug movement between the two conformations. Remarkably, the structures uncover lipid molecules bound in or near the transporter vestibule along with the drugs. MD trajectories from the IF structure show that these lipids stimulate drug diso

SUBMITTER: Tang Q 

PROVIDER: S-EPMC12644906 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature