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Inhibition and transport mechanisms of the ABC transporter hMRP5

Author

Listed:
  • Ying Huang

    (Shenzhen
    Shenzhen)

  • Chenyang Xue

    (Shenzhen
    Shenzhen)

  • Ruiqian Bu

    (Shenzhen
    Shenzhen)

  • Cang Wu

    (Shenzhen
    Shenzhen)

  • Jiachen Li

    (Zhejiang University)

  • Jinqiu Zhang

    (Zhejiang University)

  • Jinyu Chen

    (Zhejiang University)

  • Zhaoying Shi

    (Shenzhen)

  • Yonglong Chen

    (Shenzhen)

  • Yong Wang

    (Zhejiang University
    International Campus of Zhejiang University)

  • Zhongmin Liu

    (Shenzhen
    Shenzhen
    Shenzhen)

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.

Suggested Citation

  • Ying Huang & Chenyang Xue & Ruiqian Bu & Cang Wu & Jiachen Li & Jinqiu Zhang & Jinyu Chen & Zhaoying Shi & Yonglong Chen & Yong Wang & Zhongmin Liu, 2024. "Inhibition and transport mechanisms of the ABC transporter hMRP5," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49204-1
    DOI: 10.1038/s41467-024-49204-1
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    References listed on IDEAS

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    1. Michael L. Oldham & Richard K. Hite & Alanna M. Steffen & Ermelinda Damko & Zongli Li & Thomas Walz & Jue Chen, 2016. "A mechanism of viral immune evasion revealed by cryo-EM analysis of the TAP transporter," Nature, Nature, vol. 529(7587), pages 537-540, January.
    2. Nitesh Kumar Khandelwal & Thomas M. Tomasiak, 2024. "Structural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
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