biostudies-literatureAlam AOncosuisseSwiss National Science FoundationNational Institutes of HealthNIGMS NIH HHS753-756https://www.ebi.ac.uk/biostudies/studies/S-EPMC6800160biostudies-literatureUnknown363(6428)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 contrScience (New York, N.Y.)Structural insight into substrate and inhibitor discrimination by human P-glycoprotein.PMC6800160P20GM109091P20 GM109091Broude EAlam ALocher KPRoninson IKowal JfalseStructural insight into substrate and inhibitor discrimination by human P-glycoprotein.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 contr2019-01-01T00:00:00Z2019 Feb2026-05-04T17:12:43.764Z2019-10-30T08:23:06ZS-EPMC68001603076556910.1126/science.aav7102