Structural highlights
Publication Abstract from PubMed
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.
Structural insight into substrate and inhibitor discrimination by human P-glycoprotein.,Alam A, Kowal J, Broude E, Roninson I, Locher KP Science. 2019 Feb 15;363(6428):753-756. doi: 10.1126/science.aav7102. PMID:30765569[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Alam A, Kowal J, Broude E, Roninson I, Locher KP. Structural insight into substrate and inhibitor discrimination by human P-glycoprotein. Science. 2019 Feb 15;363(6428):753-756. doi: 10.1126/science.aav7102. PMID:30765569 doi:http://dx.doi.org/10.1126/science.aav7102
