ATP Binding Enables Substrate Release from Multidrug Resistance Protein 1

Cell. 2018 Jan 11;172(1-2):81-89.e10. doi: 10.1016/j.cell.2017.12.005. Epub 2017 Dec 28.

Abstract

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: ABC transporter; ABCC1; MRP1; cryo-EM; multidrug resistance; outward facing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism*
  • Animals
  • Binding Sites
  • HEK293 Cells
  • Humans
  • Leukotriene C4 / chemistry
  • Leukotriene C4 / metabolism*
  • Protein Binding
  • Protein Multimerization
  • Sf9 Cells
  • Spodoptera

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Leukotriene C4
  • Adenosine Triphosphate