Folate receptors (FRα, FRβ and FRγ) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FRα, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions1,2,3. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FRα antibodies, high-affinity antifolates4,5, folate-based imaging agents and folate-conjugated drugs and toxins6,7,8. To understand how folate binds its receptors, we determined the crystal structure of human FRα in complex with folic acid at 2.8 Å resolution. FRα has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FRα binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system.
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Protein Data Bank
The structure of FRα bound to folic acid has been deposited in the Protein Data Bank under the accession code 4LRH.
We thank Y. Jones for the pHL-Fc plasmid and H. L. Monaco for providing the chicken riboflavin-binding protein coordinates. The atomic coordinates have been deposited in the Protein Data Bank with accession codes listed in Supplementary Table 1. We thank staff members of the Life Science Collaborative Access Team of the Advanced Photon Source (APS) for assistance in data collection at the beam lines of sector 21, which is in part funded by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817). Use of APS was supported by the Office of Science of the US Department of Energy, under contract no. DE-AC02-06CH11357. This work was supported by the Jay and Betty Van Andel Foundation, and work by the Yong, Xu and Melcher laboratories is supported by the American Asthma Foundation, Ministry of Science and Technology (China) grants 2012ZX09301001-005 and 2012CB910403, Amway (China), by National Institutes of Health grants R01 DK071662 (H.E.X.) and R01 GM102545 (K.M.), and by the National Research Foundation Singapore under its Clinician Scientist Award NMRC/CSA/026/2011 (E.-L.Y.). C.C. is recipient of the NUS Graduate School for Integrative Sciences and Engineering Scholarship.
This file contains Supplementary Figures 1-9 and Supplementary Table 1. Supplementary Table 1 was added on 01 August 2013.