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Publication Abstract from PubMed

P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 A. In this study, we have obtained a higher resolution (2.5 A) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp.

Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules.,Hamaguchi-Suzuki N, Adachi N, Moriya T, Yasuda S, Kawasaki M, Suzuki K, Ogasawara S, Anzai N, Senda T, Murata T Biochem Biophys Res Commun. 2024 May 21;709:149855. doi: , 10.1016/j.bbrc.2024.149855. Epub 2024 Mar 28. PMID:38579618^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.