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 () and Zhongmin Liu ()
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Ying Huang: Shenzhen
Chenyang Xue: Shenzhen
Ruiqian Bu: Shenzhen
Cang Wu: Shenzhen
Jiachen Li: Zhejiang University
Jinqiu Zhang: Zhejiang University
Jinyu Chen: Zhejiang University
Zhaoying Shi: Shenzhen
Yonglong Chen: Shenzhen
Yong Wang: Zhejiang University
Zhongmin Liu: Shenzhen

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49204-1

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