Structural insight into substrate and inhibitor discrimination by human P-glycoprotein

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Science  15 Feb 2019:
Vol. 363, Issue 6428, pp. 753-756
DOI: 10.1126/science.aav7102

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To transport or not to transport

Therapeutic drug delivery into cells is complicated by membrane proteins like ABCB1 (also termed P-glycoprotein) that shuttle diverse compounds out of cells. Alam et al. determined high-resolution cryo–electron microscopy structures of ABCB1 bound either to a substrate, the cancer drug Taxol, or to the ABCB1 inhibitor zosuquidar. The conformational changes that facilitate drug transport are caused by hydrolysis of adenosine triphosphate (ATP). The structures show that, although Taxol and zosquidar bind to the same site, subtle structural differences lead to altered conformations of the nucleotide binding domains that are responsible for ATP hydrolysis.

Science, this issue p. 753


ABCB1, also known as 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 3.5-angstrom cryo–electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) 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 toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the adenosine triphosphate–hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport.

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