Structural insight into substrate and inhibitor discrimination by human P-glycoprotein
ABCB1 is a key multidrug exporter in humans that uses ATP to extrude a large array of chemically and structurally diverse compounds across cellular membranes. A recent “Science” paper by the Locher group (IMBB) sheds lights on the chemistry governing substrate and inhibitor binding in human ABCB1.
ABCB1/P-glycoprotein actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5Å cryo-EM structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified towards the NBDs, revealing how the plasticity of the drug-binding site controls the dynamics of the ATP-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.
Link to the publication in external page Science.