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

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.

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