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Title | Structural insight into substrate and inhibitor discrimination by human P-glycoprotein. |
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Journal, issue, pages | Science, Vol. 363, Issue 6428, Page 753-756, Year 2019 |
Publish date | Feb 15, 2019 |
Authors | Amer Alam / Julia Kowal / Eugenia Broude / Igor Roninson / Kaspar P Locher / |
PubMed Abstract | 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 ...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. |
External links | Science / PubMed:30765569 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.5 - 3.9 Å |
Structure data | EMDB-4536, PDB-6qee: EMDB-4539, PDB-6qex: EMDB-4540: EMDB-4541: |
Chemicals | ChemComp-NAG: ChemComp-ZQU: ChemComp-CLR: ChemComp-3PE: ChemComp-TA1: |
Source |
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Keywords | MEMBRANE PROTEIN / ABCB1 / p-glycoprotein / p-gp / multidrug transporter / ABC transporter / zosuquidar / membrane transporter / multidrug exporter |