Shanghai Institute of Materia Medica (SIMM) researchers have mapped the complex molecular structure of a folate receptor, a drug target for a number of cancers and other diseases, a first-of-its-kind discovery that may lead to the development of more precise, consistent and effective treatments.

Folate receptors are cell surface receptors that bind to and transport folic acid (a water-soluble vitamin belonging to the B-complex group of vitamins – vitamin B9 – found in leafy green vegetables, liver and kidney), and a variety of folic acid derivatives. Folate deficiency is associated with many diseases, including cardiovascular disease and cancers, and folates are also essential in embryos for the normal development of the neural tube, a hollow structure from which the brain and spinal cord form.

Folates are required by all living cells for the synthesis of nucleic acids, and therefore for cell proliferation. Rapidly dividing cells, such as cancer cells, are therefore much more dependent on folates than quiescent body cells, and this vulnerability of cancer cells has been therapeutically exploited since the 1940s, when antifolates (folic acid-mimicking molecules that inhibit folate-metabolizing enzymes) were used as the first chemotherapeutic agents.　

In addition to folate requirement, folate uptake is also highly selective. In adult tissues, folates are mainly taken up with relatively low affinity by a ubiquitously expressed membrane channel. In contrast, FRα is significantly expressed only in cells important for embryonic development (placenta) and folate resorption (kidney) and allows very high affinity folate uptake to essentially suck up folates under folate-limiting conditions. Many tumors therefore hijack FRα and express it at very high levels to meet their folate demand – in fact so much, that cancer cells can be selectively killed by targeting toxins to FRα.

Importantly, clinically used antifolates are not preferentially taken up by tumor-selective FRα, but ubiquitously. This causes severe side effects by also killing non-malignant proliferative cells, such as bone marrow cells and hair follicles (the latter being responsible for the characteristic hair loss upon chemotherapy). The new structure of FRα bound to folic acid, as well as a previous structure of the antifolate methotrexate bound to a folate-metabolizing enzyme, provide atomic-level details of binding that can be exploited to rationally design novel antifolates that are selectively taken up by FRα-overexpressing cancer cells. If successful, these drugs would greatly reduce the toxic side effects of antifolate chemotherapeutics, by inhibiting proliferation selectively in FRα-overexpressing cancer cells.

To understand how folate binds its receptors, SIMM and VAI researchers determined the crystal structure of human FRα in complex with folic acid at 2.8 ? resolution. They determined that FRα has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprising residues that are conserved in all receptor subtypes.

"Despite intense research on the folate structure–activity relationship, the molecular basis for the high-affinity recognition of folates by FRα has remained elusive, owing to the technical difficulties in expression, purification and crystallization of FRα for structural studies,” said H. Eric Xu Ph.D., Primary Investigator and Distinguished Director of the VARI/SIMM Research Center, and lead author of the study.

The paper was published online yesterday in the journal Nature, scientists presented the crystal structure of the human folate receptor FRα in complex with folic acid.

The study involved researchers from VARI/SIMM Center, Center for Structure and Function of Drug Targets, and CAS-Key Laboratory of Receptor Research, of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Van Andel Institute’s Program for Structural Biology and Drug Discovery, the National University of Singapore Graduate School for Integrative Science and Engineering, and the Life Sciences Collaborative Access Team of the Synchrotron Research Center at Northwestern University. Yi Wei Ph.D., the postdoctoral of H. Eric Xu from Shanghai Institute of Materia Medica, participated in the study as co-author.

This work was strongly supported by the Organization Department of the Central Committee of the CPC “Thousand Talents program”, Chinese Academy of Sciences, National Natural Science Foundation of China, Ministry of Science, major projects of new drugs, the United States Van Andel Research Institute and the China Amway.

Paper link: http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature12327.pdf