EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Cryo-EM of human P-glycoprotein reveals an intermediate occluded conformation during active drug transport.
ジャーナル・号・ページ	Nat Commun, Vol. 16, Issue 1, Page 3619, Year 2025
掲載日	2025年4月16日
著者	Alan T Culbertson / Maofu Liao /
PubMed 要旨	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 ...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.
リンク	Nat Commun / PubMed:40240353 / PubMed Central
手法	EM (単粒子)
解像度	3.9 - 6.4 Å
構造データ	40226 8gmg EMDB-40226, PDB-8gmg: CryoEM structure of P-Glycoprotein in Apo state 手法: EM (単粒子) / 解像度: 4.3 Å 40227 8gmj EMDB-40227, PDB-8gmj: CryoEM structure of P-Glycoprotein in collapsed closed state under continuous turnover conditions with verapamil 手法: EM (単粒子) / 解像度: 4.4 Å 40258 8sa0 EMDB-40258, PDB-8sa0: CryoEM structure of P-Glycoprotein in occluded closed state under continuous turnover conditions with verapamil 手法: EM (単粒子) / 解像度: 4.1 Å 40259 8sa1 EMDB-40259, PDB-8sa1: CryoEM structure of P-Glycoprotein in inward facing 2 state under continuous turnover conditions with verapamil 手法: EM (単粒子) / 解像度: 4.4 Å 40292 8sb7 EMDB-40292, PDB-8sb7: CryoEM structure of P-Glycoprotein in inward facing 1 state under continuous turnover conditions with verapamil 手法: EM (単粒子) / 解像度: 4.0 Å 40293 8sb8 EMDB-40293, PDB-8sb8: CryoEM structure of P-Glycoprotein in collapsed closed state with vanadate 手法: EM (単粒子) / 解像度: 3.9 Å 40294 8sb9 EMDB-40294, PDB-8sb9: CryoEM structure of P-Glycoprotein in inward facing 1 state under continuous turnover conditions with vinblastine 手法: EM (単粒子) / 解像度: 4.1 Å 40295 8sba EMDB-40295, PDB-8sba: CryoEM structure of P-Glycoprotein in inward facing 2 state under continuous turnover conditions with vinblastine 手法: EM (単粒子) / 解像度: 3.9 Å EMDB-40326: CryoEM structure of P-Glycoprotein in inward facing state with MgATP and vanadate 手法: EM (単粒子) / 解像度: 4.5 Å EMDB-40340: CryoEM structure of P-Glycoprotein in inward facing state 1 with vinblastine 手法: EM (単粒子) / 解像度: 5.3 Å EMDB-40341: CryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine 手法: EM (単粒子) / 解像度: 4.5 Å EMDB-40342: CryoEM structure of P-Glycoprotein in closed 1 state under continuous turnover conditions with vinblastine 手法: EM (単粒子) / 解像度: 5.6 Å EMDB-40343: CryoEM structure of P-Glycoprotein in closed 2 state under continuous turnover conditions with vinblastine 手法: EM (単粒子) / 解像度: 6.4 Å
化合物	ChemComp-MG: Unknown entry ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, エネルギー貯蔵分子YM ChemComp-I6H: Dexverapamil ChemComp-AOV: ADP ORTHOVANADATE / エネルギー貯蔵分子類似体YM ChemComp-VLB: (2ALPHA,2'BETA,3BETA,4ALPHA,5BETA)-VINCALEUKOBLASTINE / 薬剤, 化学療法薬*YM
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN / multidrug resistance / ABC transporter / membrane protein / transporter / Transporter.