Cell
Volume 172, Issues 1–2, 11 January 2018, Pages 81-89.e10
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Article
ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1

https://doi.org/10.1016/j.cell.2017.12.005Get rights and content
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Highlights

  • Cryo-EM structure of ATP-bound, outward-facing MRP1 at 3.1 Å

  • Substrate-binding site rearranges in outward-facing state to relinquish affinity

  • Substrate is released upon NBD dimerization prior to ATP hydrolysis

Summary

The multidrug resistance protein MRP1 is an ATP-driven pump that confers resistance to chemotherapy. Previously, we have shown that intracellular substrates are recruited to a bipartite binding site when the transporter rests in an inward-facing conformation. A key question remains: how are high-affinity substrates transferred across the membrane and released outside the cell? Using electron cryomicroscopy, we show here that ATP binding opens the transport pathway to the extracellular space and reconfigures the substrate-binding site such that it relinquishes its affinity for substrate. Thus, substrate is released prior to ATP hydrolysis. With this result, we now have a complete description of the conformational cycle that enables substrate transfer in a eukaryotic ABC exporter.

Keywords

MRP1
ABCC1
multidrug resistance
ABC transporter
outward facing
cryo-EM

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