Structural basis of antifolate recognition and transport by PCFT

Nature. 2021 Jul;595(7865):130-134. doi: 10.1038/s41586-021-03579-z.

Joanne L Parker ^# ¹, Justin C Deme ^# ² ³ ⁴, Gabriel Kuteyi ⁵, Zhiyi Wu ⁵, Jiandong Huo ⁶ ⁷ ⁸, I David Goldman ⁹, Raymond J Owens ⁶ ⁷ ⁸, Philip C Biggin ⁵, Susan M Lea ¹⁰ ¹¹ ¹², Simon Newstead ¹³ ¹⁴

Affiliations

1 Department of Biochemistry, University of Oxford, Oxford, UK. joanne.parker@bioch.ox.ac.uk.
2 Dunn School of Pathology, University of Oxford, Oxford, UK.
3 Central Oxford Structural Molecular Imaging Centre, University of Oxford, Oxford, UK.
4 Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
5 Department of Biochemistry, University of Oxford, Oxford, UK.
6 Structural Biology, The Rosalind Franklin Institute, Didcot, UK.
7 Division of Structural Biology, The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
8 Protein Production UK, The Research Complex at Harwell, Didcot, UK.
9 Departments of Molecular Pharmacology and Medicine, Albert Einstein College of Medicine, New York, NY, USA.
10 Dunn School of Pathology, University of Oxford, Oxford, UK. susan.lea@nih.gov.
11 Central Oxford Structural Molecular Imaging Centre, University of Oxford, Oxford, UK. susan.lea@nih.gov.
12 Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. susan.lea@nih.gov.
13 Department of Biochemistry, University of Oxford, Oxford, UK. simon.newstead@bioch.ox.ac.uk.
14 The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK. simon.newstead@bioch.ox.ac.uk.
# Contributed equally.

PMID: 34040256 DOI: 10.1038/s41586-021-03579-z

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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