Structural basis of antifolate recognition and transport by PCFT

Author:

Parker, Joanne L.

Deme,Justin

Kuteyi, Gabriel

Wu, Zhiyi

Huo, Jiandong

Goldman, I. David

Owens, Raymond J.

Biggin, Philip C.

Lea,Susan

Newstead, Simon
Author Address

Univ Oxford, Dept Biochem, Oxford, England.Univ Oxford, Dunn Sch Pathol, Oxford, England.Univ Oxford, Cent Oxford Struct Mol Imaging Ctr, Oxford, England.NCI, Struct Biol Ctr, Ctr Canc Res, Frederick, MD 21701 USA.Rosalind Franklin Inst, Struct Biol, Didcot, Oxon, England.Univ Oxford, Div Struct Biol, Wellcome Ctr Human Genet, Oxford, England.Prot Prod UK, Res Complex Harwell, Didcot, Oxon, England.Albert Einstein Coll Med, Dept Mol Pharmacol, New York, NY USA.Albert Einstein Coll Med, Dept Med, New York, NY USA.Univ Oxford, Kavli Inst Nanosci Discovery, Oxford, England.

Abstract:

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(1,2). Folate deficiency is associated with a number of developmental, immune and neurological disorders(3-5). Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body(3,6). The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus(4,7), and is an important route for the delivery of antifolate drugs in cancer chemotherapy(8-10). 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.

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