Structural basis of antifolate recognition and transport by PCFT

Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine . Folate deficiency is associated with a number of developmental, immune and neurological disord...

Full description

Saved in:
Bibliographic Details
Published inNature (London) Vol. 595; no. 7865; pp. 130 - 134
Main Authors Parker, Joanne L, Deme, Justin C, Kuteyi, Gabriel, Wu, Zhiyi, Huo, Jiandong, Goldman, I David, Owens, Raymond J, Biggin, Philip C, Lea, Susan M, Newstead, Simon
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.07.2021
Subjects
Amino acids
Antifolate agents
Apoproteins - chemistry
Apoproteins - metabolism
Apoproteins - ultrastructure
Binding sites
Biological Transport
Cancer therapies
Cryoelectron Microscopy
Drug delivery
Drugs
Electron microscopy
Folic acid
Folic Acid Antagonists - chemistry
Folic Acid Antagonists - metabolism
Humans
Immunosuppressive agents
Ligands
Metabolism
Microscopy
Models, Molecular
Mutation
Nucleic acids
Pemetrexed - chemistry
Pemetrexed - metabolism
Proteins
Proton-Coupled Folate Transporter - chemistry
Proton-Coupled Folate Transporter - metabolism
Proton-Coupled Folate Transporter - ultrastructure
Protons
Recognition
Salt
Substrates
Vitamin B
Vitamin deficiency
Online AccessGet full text

Cover

More Information
Summary:Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine . Folate deficiency is associated with a number of developmental, immune and neurological disorders . Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body . The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus , and is an important route for the delivery of antifolate drugs in cancer chemotherapy . How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Author contributions J.L.P. and S.N. conceived the project. G.K. maintained cell stocks, and undertook large-scale expression and tissue culture. J.L.P. and S.N. performed all protein preparation. J.H. and R.J.O. screened the Abcore library. J.C.D. and S.M.L. performed all cryo-EM sample processing, data collection and image analysis. J.C.D., S.M.L. and S.N. constructed the atomic models. I.D.G. contributed the HeLa-derived cell line HeLa R1-11, and provided insights into human mutations and physiology. J.L.P. conducted all transport and biochemical assays. Z.W. and P.C.B. performed all molecular dynamics analysis. J.L.P. and S.N. wrote the manuscript and prepared figures, with contributions and discussions from Z.W., I.D.G., P.C.B., J.C.D. and S.M.L. G.K. and Z.W. contributed equally to this work.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-021-03579-z