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ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1
Zachary Lee Johnson1, Jue Chen1
1Laboratory of Membrane Biology and Biophysics, The Rockefeller University and Howard Hughes Medical Institute, New York, NY 10065, USA.
Cell
|January 2, 2018
Summary
Multidrug resistance protein MRP1 uses ATP to pump chemotherapy drugs out of cells. ATP binding opens the transporter, releasing drugs before ATP is used, completing the transport cycle.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette (ABC) transporter.
- MRP1 confers resistance to chemotherapy by extruding drugs from cells.
- Previous studies showed substrate recruitment to an inward-facing binding site.
Purpose of the Study:
- To elucidate the mechanism of high-affinity substrate transfer across the membrane by MRP1.
- To describe the conformational changes involved in substrate release from MRP1.
Main Methods:
- Electron cryomicroscopy (cryo-EM) was used to visualize MRP1.
- Structural analysis of MRP1 in different conformational states.
Main Results:
- ATP binding reconfigures the substrate-binding site, reducing its affinity.
- The transport pathway opens to the extracellular space upon ATP binding.
- Substrate release occurs before ATP hydrolysis.
Conclusions:
- A complete conformational cycle for substrate transport by MRP1 is now described.
- Understanding this cycle is crucial for developing strategies to overcome multidrug resistance.
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