Abstract
AbstractHuman multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs.
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
Reference51 articles.
1. Thomas, C. & Tampé, R. Multifaceted structures and mechanisms of ABC transport systems in health and disease. Curr. Opin. Struct. Biol. 51, 116–128 (2018).
2. Rees, D. C., Johnson, E. & Lewinson, O. ABC transporters: the power to change. Nat. Rev. Mol. Cell. Biol. 10, 218–227 (2009).
3. Wang, J. Q. et al. Multidrug resistance proteins (MRPs): structure, function and the overcoming of cancer multidrug resistance. Drug Resist. Updat. 54, 100743 (2021).
4. Grube, M., Hagen, P. & Jedlitschky, G. Neurosteroid transport in the brain: role of ABC and SLC transporters. Front. Pharmacol. 9, 354 (2018).
5. Kool, M. et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 57, 3537–3547 (1997).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献