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TitleMolecular basis of SLC19A1-mediated folate and cyclic dinucleotide transport.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 3146, Year 2025
Publish dateApr 2, 2025
AuthorsQixiang Zhang / Xuyuan Zhang / Kexin Liu / Yalan Zhu / Xiaohua Nie / Junxiao Ma / Panpan Sun / Zhaolong Li / Yina Gao / Songqing Liu / Ang Gao / Liguo Zhang / Pu Gao /
PubMed AbstractThe solute carrier protein SLC19A1 is crucial for transporting folate nutrients, antifolate chemotherapeutics, and more recently cyclic dinucleotides (CDNs) immune transmitters, influencing various ...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.
External linksNat Commun / PubMed:40175380 / PubMed Central
MethodsEM (single particle)
Resolution2.94 - 3.74 Å
Structure data

EMDB-61690, PDB-9joz:
outward-open hSLC19A1
Method: EM (single particle) / Resolution: 2.94 Å

EMDB-61756, PDB-9jri:
outward-open hSLC19A1 + 5-MTHF
Method: EM (single particle) / Resolution: 3.43 Å

EMDB-61758, PDB-9jrk:
outward-open hSLC19A1 + MTX
Method: EM (single particle) / Resolution: 3.44 Å

EMDB-61759, PDB-9jrl:
outward-open hSLC19A1 + PT523
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-61760, PDB-9jrm:
outward-open hSLC19A1 + 2'3'-CDAS
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-61761, PDB-9jrn:
outward-open hSLC19A1 + TPP
Method: EM (single particle) / Resolution: 3.74 Å

Chemicals

ChemComp-C2F:
5-METHYL-5,6,7,8-TETRAHYDROFOLIC ACID

ChemComp-MTX:
METHOTREXATE / chemotherapy*YM

ChemComp-COP:
N-(4-CARBOXY-4-{4-[(2,4-DIAMINO-PTERIDIN-6-YLMETHYL)-AMINO]-BENZOYLAMINO}-BUTYL)-PHTHALAMIC ACID

ChemComp-GJF:
(1~{R},3~{S},6~{R},8~{R},9~{R},10~{S},12~{S},15~{R},17~{R},18~{R})-8,17-bis(6-aminopurin-9-yl)-3,12-bis(oxidanylidene)-3,12-bis(sulfanyl)-2,4,7,11,13,16-hexaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.2.1.0^{6,10}]octadecane-9,18-diol

ChemComp-TPP:
THIAMINE DIPHOSPHATE

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / outward-open hSLC19A1

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