8WI2

RD-hMRP5-inward open

8WI2 の概要

• エントリーDOI: 10.2210/pdb8wi2/pdb
• EMDBエントリー: 37555
• 分子名称: ATP-binding cassette sub-family C member 5, CYS-GLN-ASP-ALA-LEU-GLU-THR-ALA-ALA-ARG-ALA-GLU-GLY-LEU-SER-LEU-ASP-ALA-SER (2 entities in total)
• 機能のキーワード: rd-hmrp5-inward open, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 151195.85

構造登録者

Liu, Z.M.,Huang, Y. (登録日: 2023-09-24, 公開日: 2024-07-03, 最終更新日: 2025-07-23)

主引用文献

Huang, Y.,Xue, C.,Bu, R.,Wu, C.,Li, J.,Zhang, J.,Chen, J.,Shi, Z.,Chen, Y.,Wang, Y.,Liu, Z.
Inhibition and transport mechanisms of the ABC transporter hMRP5.
Nat Commun, 15:4811-4811, 2024

PubMed Abstract: Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.

PubMed: 38844452
DOI: 10.1038/s41467-024-49204-1

実験手法

ELECTRON MICROSCOPY (4.06 Å)