9JRK

outward-open hSLC19A1 + MTX

Summary for 9JRK

• Entry DOI: 10.2210/pdb9jrk/pdb
• EMDB information: 61758
• Descriptor: Soluble cytochrome b562,Reduced folate transporter,fusion protein, METHOTREXATE (2 entities in total)
• Functional Keywords: outward-open hslc19a1, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 1
• Total formula weight: 77974.39

Authors

Zhang, Q.X.,Liu, K.X.,Gao, P. (deposition date: 2024-09-29, release date: 2025-02-26, Last modification date: 2025-04-23)

Primary citation

Zhang, Q.,Zhang, X.,Liu, K.,Zhu, Y.,Nie, X.,Ma, J.,Sun, P.,Li, Z.,Gao, Y.,Liu, S.,Gao, A.,Zhang, L.,Gao, P.
Molecular basis of SLC19A1-mediated folate and cyclic dinucleotide transport.
Nat Commun, 16:3146-3146, 2025

PubMed 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.

PubMed: 40175380
DOI: 10.1038/s41467-025-58378-1

Experimental method

ELECTRON MICROSCOPY (3.44 Å)