8SBA

CryoEM structure of P-Glycoprotein in inward facing 2 state under continuous turnover conditions with vinblastine

8SBA の概要

• エントリーDOI: 10.2210/pdb8sba/pdb
• EMDBエントリー: 40295
• 分子名称: ATP-dependent translocase ABCB1, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: multidrug resistance, abc transporter, membrane protein, transporter, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 144329.70

構造登録者

Culbertson, A.,Liao, M. (登録日: 2023-04-02, 公開日: 2025-04-23, 最終更新日: 2025-06-04)

主引用文献

Culbertson, A.T.,Liao, M.
Cryo-EM of human P-glycoprotein reveals an intermediate occluded conformation during active drug transport.
Nat Commun, 16:3619-3619, 2025

PubMed Abstract: P-glycoprotein (Pgp) is an important human multidrug transporter that contributes to pharmacokinetics and multidrug resistance. Despite decades of study, the conformation transition cycle of Pgp undergoing active drug transport is not defined, thus the precise relevance of all available Pgp structures to uninterrupted multidrug transport remains unclear. Here, we use cryo-EM of membrane-embedded human Pgp under continuous turnover conditions to analyze the conformational ensembles of Pgp transporting distinct substrates. These results delineate multiple conformations including inward-facing and closed conformations, highlighting the occluded conformation as a critical intermediate state between transporter closure and substrate release. A combination of structural, functional, and computational studies reveals the transmembrane helices 4 and 10 undergoing drastic rearrangement to coordinate substrate binding, occlusion, and release, and identifies a peripheral site involved in substrate capture and Pgp inhibition. Together, our results provide a set of snapshots of Pgp undergoing continuous drug transport, unveiling the intricate interplay between transporter dynamics and drug movement, and shed light on the mechanism of polyspecificity.

PubMed: 40240353
DOI: 10.1038/s41467-025-58561-4

実験手法

ELECTRON MICROSCOPY (3.9 Å)