Despite a flurry of mammalian ATP binding cassette (ABC) transporter structures in the last 2 years the Holy Grail has still been to determine how these diverse proteins interact with their transport substrates. Jue Chen and colleagues at the Rockefeller have now accomplished this for the multidrug resistance protein-1 (MRP1/ABCC1) using advances in high resolution cryo-electron microscopy to show the structures of substrate-free and leukotriene C4 bound protein [1]. The paper also lays the foundation for revealing the structural basis for multidrug transport by MRP1 (which is a confounding factor for some chemotherapies) as the flexible substrate binding cavity in the membrane has both polar and a hydrophobic sub-pockets enabling it to interact with chemically diverse drugs. Whether this structural data enables the design of clinically-relevant MRP1 inhibitors will now be the focus of much research.
[1] Johnson Z.L., Chen J. (2017). Structural Basis of Substrate Recognition by the Multidrug Resistance Protein MRP1. Cell. pii: S0092-8674(17)30131-9. [PMID: 28238471]
Comments by Prof. Ian Kerr, University of Nottingham (@iankerr_science)
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