Substrate recognition diversity and transport dynamics of ABCC1

Panpan Sun, Kexin Liu, Linnan Zhang, Qixiang Zhang, Yina Gao, Zhaolong Li, Yalan Zhu, Songqing Liu, Liguo Zhang, Ang Gao and Pu Gao ()
Additional contact information
Panpan Sun: Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
Kexin Liu: Chinese Academy of Sciences, National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics
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
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65501-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65501-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65501-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().