8DEP

Cryo-EM structure of the human reduced folate carrier, apo condition

Summary for 8DEP

• Entry DOI: 10.2210/pdb8dep/pdb
• EMDB information: 26155 26156 27394
• Descriptor: Reduced folate transporter,Soluble cytochrome b562, Digitonin (2 entities in total)
• Functional Keywords: reduced folate carrier, membrane protein, membrane transporter, methotrexate, slc19a1, solute carrier family 19, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 79714.44

Authors

Wright, N.J.,Fedor, J.G.,Lee, S.-Y. (deposition date: 2022-06-21, release date: 2022-09-21, Last modification date: 2024-06-12)

Primary citation

Wright, N.J.,Fedor, J.G.,Zhang, H.,Jeong, P.,Suo, Y.,Yoo, J.,Hong, J.,Im, W.,Lee, S.Y.
Methotrexate recognition by the human reduced folate carrier SLC19A1.
Nature, 609:1056-1062, 2022

PubMed 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 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.

PubMed: 36071163
DOI: 10.1038/s41586-022-05168-0

Experimental method

ELECTRON MICROSCOPY (3.6 Å)