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Molecular structure of human P-glycoprotein in the ATP-bound, outward-…

  • 저널명Science, 359(6378):915-919. doi: 10.1126/science.aar7389
    • 담당교수Youngjin Kim
    • 조회244
    • 작성자최고관리자
    • 2020-03-02


    ■ Abstract

    The multidrug transporter permeability (P)–glycoprotein is an adenosine triphosphate (ATP)–binding cassette exporter responsible for clinical resistance to chemotherapy.

    P-glycoprotein extrudes toxic molecules and drugs from cells through ATP-powered conformational changes. Despite decades of effort, only the structures of the inwardfacing conformation of P-glycoprotein are available. Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo–electron microscopy at 3.4-angstrom resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release. The structure evokes a model in which the dynamic nature of P-glycoprotein enables translocation of a large variety of substrates.