6QEE

Nanodisc reconstituted Human-mouse chimeric ABCB1 (ABCB1HM)-EQ mutant in complex with UIC2 Fab and Zosuquidar.

Summary for 6QEE

• Entry DOI: 10.2210/pdb6qee/pdb
• EMDB information: 4536
• Descriptor: ABCB1HM-EQ, UIC2 Antigen Binding Fragment Light chain, UIC2 Antigen Binding Fragment Heavy Chain, ... (7 entities in total)
• Functional Keywords: abcb1, p-glycoprotein, p-gp, multidrug transporter, abc transporter, zosuquidar, membrane transporter, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 197503.62

Authors

Alam, A. (deposition date: 2019-01-07, release date: 2019-02-27, Last modification date: 2025-07-09)

Primary citation

Alam, A.,Kowal, J.,Broude, E.,Roninson, I.,Locher, K.P.
Structural insight into substrate and inhibitor discrimination by human P-glycoprotein.
Science, 363:753-756, 2019

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 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.

PubMed: 30765569
DOI: 10.1126/science.aav7102

Experimental method

ELECTRON MICROSCOPY (3.9 Å)