Inhibition and transport mechanisms of the ABC transporter hMRP5.

Ying Huang, Chenyang Xue, Ruiqian Bu, Cang Wu, Jiachen Li, Jinqiu Zhang, Jinyu Chen, Zhaoying Shi, Yonglong Chen, Yong Wang, Zhongmin Liu

Nature communications 2024 Jun 06

filter terms:

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. © 2024. The Author(s).

Citation

Ying Huang, Chenyang Xue, Ruiqian Bu, Cang Wu, Jiachen Li, Jinqiu Zhang, Jinyu Chen, Zhaoying Shi, Yonglong Chen, Yong Wang, Zhongmin Liu. Inhibition and transport mechanisms of the ABC transporter hMRP5. Nature communications. 2024 Jun 06;15(1):4811