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

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Science  25 Jan 2018:
eaar7389
DOI: 10.1126/science.aar7389

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Abstract

The multidrug transporter P-glycoprotein is an 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 inward-facing conformation of P-glycoprotein are available. Here we present the structure of human P-glycoprotein in the outward-facing conformation, determined by electron cryo-microscopy at 3.4-Å 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 re-orientated 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.

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