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Substrate recognition diversity and transport dynamics of ABCC1

Author

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  • Panpan Sun

    (Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
    University of Chinese Academy of Sciences)

  • Kexin Liu

    (Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
    University of Chinese Academy of Sciences)

  • Linnan Zhang

    (Shandong First Medical University & Shandong Academy of Medical Sciences, Medical Science and Technology Innovation Center)

  • Qixiang Zhang

    (Beijing Institute of Technology, School of Life Sciences)

  • Yina Gao

    (Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics)

  • Zhaolong Li

    (Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
    University of Chinese Academy of Sciences)

  • Yalan Zhu

    (Beijing Institute of Technology, School of Life Sciences)

  • Songqing Liu

    (Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics)

  • Liguo Zhang

    (Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
    University of Chinese Academy of Sciences)

  • Ang Gao

    (Beijing Institute of Technology, School of Life Sciences)

  • Pu Gao

    (Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
    University of Chinese Academy of Sciences
    Shandong First Medical University & Shandong Academy of Medical Sciences, Medical Science and Technology Innovation Center)

Abstract

ABCC1 is an ATP-binding cassette (ABC) transporter that exports diverse endogenous and exogenous substrates, conferring resistance to many anticancer drugs and mediating various physiological functions. Here, we present ten cryo-EM structures of ABCC1 in different functional states, providing systematic insights into its substrate recognition diversity and transport dynamics. ABCC1 utilizes a plastic bipartite substrate-binding pocket and a substrate-induced conformational flexibility to accommodate molecules with diverse properties, including bimolecular glutathione (GSH)-substrate pairs, GSH conjugates, and GSH-independent cyclic dinucleotides. A herein characterized substrate-releasing intermediate state reveals ATP-mediated overall conformational transitions and detailed pocket reorganization during substrate loading, pre-release, and post-release. Unexpectedly, we identify a sequential nucleotide release mechanism where the hydrolysis product ADP, rather than unhydrolyzed ATP, releases first, priming the transporter for turnover and resetting. Complemented by mutagenesis and functional assays, these findings provide a complete framework for understanding ABCC1’s molecular basis and offer a foundation for developing next-generation modulators.

Suggested Citation

  • Panpan Sun & Kexin Liu & Linnan Zhang & Qixiang Zhang & Yina Gao & Zhaolong Li & Yalan Zhu & Songqing Liu & Liguo Zhang & Ang Gao & Pu Gao, 2025. "Substrate recognition diversity and transport dynamics of ABCC1," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65501-9
    DOI: 10.1038/s41467-025-65501-9
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