7A65

Nanodisc reconstituted, drug-free human ABCB1 in complex with MRK16 Fab

7A65 の概要

• エントリーDOI: 10.2210/pdb7a65/pdb
• EMDBエントリー: 11666
• 分子名称: Multidrug resistance protein 1, MRK16 Fab-fragment light chain, MRK16 Fab-fragment heavy chain, ... (4 entities in total)
• 機能のキーワード: p-glycoprotein, mdr1, nanodisc, transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 191503.70

構造登録者

Nosol, K.,Locher, K.P. (登録日: 2020-08-25, 公開日: 2020-10-14, 最終更新日: 2025-07-02)

主引用文献

Nosol, K.,Romane, K.,Irobalieva, R.N.,Alam, A.,Kowal, J.,Fujita, N.,Locher, K.P.
Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1.
Proc.Natl.Acad.Sci.USA, 117:26245-26253, 2020

PubMed Abstract: ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors.

PubMed: 33020312
DOI: 10.1073/pnas.2010264117

実験手法

ELECTRON MICROSCOPY (3.9 Å)