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Structure paper

タイトル	Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules.
ジャーナル・号・ページ	Biochem Biophys Res Commun, Vol. 709, Page 149855, Year 2024
掲載日	2024年5月21日
著者	Norie Hamaguchi-Suzuki / Naruhiko Adachi / Toshio Moriya / Satoshi Yasuda / Masato Kawasaki / Kano Suzuki / Satoshi Ogasawara / Naohiko Anzai / Toshiya Senda / Takeshi Murata /
PubMed 要旨	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. ...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 Å. In this study, we have obtained a higher resolution (2.5 Å) 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.
リンク	Biochem Biophys Res Commun / PubMed:38579618
手法	EM (単粒子)
解像度	2.49 - 2.54 Å
構造データ	38986 8y6h EMDB-38986, PDB-8y6h: P-glycoprotein in complex with UIC2 Fab and triple elacridar molecules in LMNG detergent 手法: EM (単粒子) / 解像度: 2.49 Å 38987 8y6i EMDB-38987, PDB-8y6i: P-glycoprotein in complex with UIC2 Fab and triple elacridar molecules in nanodisc 手法: EM (単粒子) / 解像度: 2.54 Å
化合物	ChemComp-R0Z: elacridar / GF-120918 ChemComp-CLR: CHOLESTEROL / コレステロ-ル / コレステロール ChemComp-3PE: 1,2-Distearoyl-sn-glycerophosphoethanolamine / DSPE / リン脂質*YM / ホスファチジルエタノールアミン
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / ABC transporter / elacridar / P-glycoprotein (P糖タンパク質)