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

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Science  23 Feb 2018:
Vol. 359, Issue 6378, pp. 915-919
DOI: 10.1126/science.aar7389

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A path to multidrug resistance

Permeability glycoprotein (PgP) uses the energy from adenosine triphosphate (ATP) hydrolysis to transport substrates out of the cell. Many of its substrates are drugs, so it plays an important role in drug resistance. Structures in the inward-facing conformation have been determined for mouse, yeast, and algal PgP. Kim and Chen present the cryo–electron microscopy structure of human PgP in an outward-facing conformation. Two ATP molecules are bound between two nucleotide-binding domains. The substrate-binding site, located in the transmembrane domain, is open to the outside of the cell, but compressed, and no substrate is bound. This suggests that ATP binding, rather than ATP hydrolysis, promotes the transition to the outward-facing conformation and substrate release.

Science, this issue p. 915

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 inward-facing 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.

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