Methotrexate recognition by the human reduced folate carrier SLC19A1

Nicholas J. Wright, Justin G. Fedor, Han Zhang, Pyeonghwa Jeong, Yang Suo, Jiho Yoo, Jiyong Hong, Wonpil Im and Seok-Yong Lee ()
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Nicholas J. Wright: Duke University School of Medicine
Justin G. Fedor: Duke University School of Medicine
Han Zhang: Lehigh University
Pyeonghwa Jeong: Duke University
Yang Suo: Duke University School of Medicine
Jiho Yoo: Duke University School of Medicine
Jiyong Hong: Duke University
Wonpil Im: Lehigh University
Seok-Yong Lee: Duke University School of Medicine

Nature, 2022, vol. 609, issue 7929, 1056-1062

Abstract: Abstract 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 division1,2. Mammals lack de novo folate synthesis pathways and thus rely on folate uptake from the extracellular milieu3. The human reduced folate carrier (hRFC, also known as SLC19A1) is the major importer of folates into the cell1,3, as well as chemotherapeutic agents such as methotrexate4–6. 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 resistance4–8. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05168-0

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