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TitleMethotrexate recognition by the human reduced folate carrier SLC19A1.
Journal, issue, pagesNature, Vol. 609, Issue 7929, Page 1056-1062, Year 2022
Publish dateSep 7, 2022
AuthorsNicholas J Wright / Justin G Fedor / Han Zhang / Pyeonghwa Jeong / Yang Suo / Jiho Yoo / Jiyong Hong / Wonpil Im / Seok-Yong Lee /
PubMed AbstractFolates are essential nutrients with important roles as cofactors in one-carbon transfer reactions, being heavily utilized in the synthesis of nucleic acids and the metabolism of amino acids during ...Folates are essential nutrients with important roles as cofactors in one-carbon transfer reactions, being heavily utilized in the synthesis of nucleic acids and the metabolism of amino acids during cell division. Mammals lack de novo folate synthesis pathways and thus rely on folate uptake from the extracellular milieu. The human reduced folate carrier (hRFC, also known as SLC19A1) is the major importer of folates into the cell, as well as chemotherapeutic agents such as methotrexate. As an anion exchanger, RFC couples the import of folates and antifolates to anion export across the cell membrane and it is a major determinant in methotrexate (antifolate) sensitivity, as genetic variants and its depletion result in drug resistance. Despite its importance, the molecular basis of substrate specificity by hRFC remains unclear. Here we present cryo-electron microscopy structures of hRFC in the apo state and captured in complex with methotrexate. Combined with molecular dynamics simulations and functional experiments, our study uncovers key determinants of hRFC transport selectivity among folates and antifolate drugs while shedding light on important features of anion recognition by hRFC.
External linksNature / PubMed:36071163 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.8 Å
Structure data

EMDB-26155, PDB-7tx6:
Cryo-EM structure of the human reduced folate carrier in complex with methotrexate
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-26156, PDB-7tx7:
Cryo-EM structure of the human reduced folate carrier
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-27394, PDB-8dep:
Cryo-EM structure of the human reduced folate carrier, apo condition
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-MTX:
METHOTREXATE / chemotherapy*YM / Methotrexate

ChemComp-AJP:
Digitonin / detergent*YM / Digitonin

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsTRANSPORT PROTEIN / transporter / reduced folate carrier / SLC19A1 / anion exchanger / Membrane transporter / SLC19 / membrane protein / methotrexate / solute carrier family 19

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