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

Amer Alam, Julia Kowal, Eugenia Broude, Igor Roninson, Kaspar P. Locher

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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 associate with drug binding and transport.

Original languageEnglish (US)
Pages (from-to)753-756
Number of pages4
JournalScience
Volume363
Issue number6428
DOIs
StatePublished - Feb 15 2019
Externally publishedYes

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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