Molecular basis of SLC19A1-mediated folate and cyclic dinucleotide transport

Qixiang Zhang, Xuyuan Zhang, Kexin Liu, Yalan Zhu, Xiaohua Nie, Junxiao Ma, Panpan Sun, Zhaolong Li, Yina Gao, Songqing Liu, Ang Gao (), Liguo Zhang () and Pu Gao ()
Additional contact information
Qixiang Zhang: Beijing Institute of Technology
Xuyuan Zhang: Chinese Academy of Sciences
Kexin Liu: Chinese Academy of Sciences
Yalan Zhu: Beijing Institute of Technology
Xiaohua Nie: Chinese Academy of Sciences
Junxiao Ma: Chinese Academy of Sciences
Panpan Sun: Chinese Academy of Sciences
Zhaolong Li: Chinese Academy of Sciences
Yina Gao: Chinese Academy of Sciences
Songqing Liu: Chinese Academy of Sciences
Ang Gao: Beijing Institute of Technology
Liguo Zhang: Chinese Academy of Sciences
Pu Gao: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract The solute carrier protein SLC19A1 is crucial for transporting folate nutrients, antifolate chemotherapeutics, and more recently cyclic dinucleotides (CDNs) immune transmitters, influencing various physiological and pathological processes. While the inward-open state of human SLC19A1 (hSLC19A1) has been previously described, key aspects regarding its conformational dynamics, substrate selectivity, and precise mechanisms underlying CDNs transport remain elusive. Using an antibody-facilitated conformation screening strategy, we present cryo-electron microscopy structures of hSLC19A1 in its outward-open state with and without bound substrates, revealing detailed mechanisms of substrate recognition and conformational changes during transport. We identify both general and specific features for folate/antifolate recognition, including an SLC19A1-specific pocket for accommodating γ-carboxylate-modified antifolates. Intriguingly, CDNs bind as monomers within the canonical pocket of outward-open hSLC19A1, contrasting with dimeric binding in inward-open structures. Together with functional assays, these findings provide a framework for developing antifolate drugs and CDN-targeted therapies, advancing our understanding of SLC19A1’s physiological and therapeutic functions.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58378-1 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_s41467-025-58378-1

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

DOI: 10.1038/s41467-025-58378-1

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 ().