Van Andel Institute discovery provides template for more effective anti-cancer drugs

Grand Rapids, Mich. (July 16, 2013) – Van Andel Institute (VAI) 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.

In an international collaboration published online this week in the journal Nature, scientists presented the crystal structure of the human folate receptor FRα in complex with folic acid.

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 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,” said Karsten Melcher, Ph.D., Head of VAI’s Laboratory of Structural Biology and Biochemistry and one of two lead authors of the study.

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 use 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 so, 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 are taken up ubiquitously.  This causes severe side effects by also killing non-malignant proliferative cells, such as bone marrow cells and hair follicles (responsible for the characteristic hair loss resulting from 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,” said first author Chen Chen, a National University of Singapore graduate student and guest student in VAI’s Laboratory of Structural Sciences.  “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, VAI researchers determined the crystal structure of human FRα in complex with folic acid at 2.8 Å 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 one of two lead authors of the study.

The study involved researchers from Van Andel Institute’s Program for Structural Biology and Drug Discovery, the National University of Singapore Graduate School for Integrative Science and Engineering, the 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, and the Life Sciences Collaborative Access Team of the Synchrotron Research Center at Northwestern University.

The paper, “Structural basis for molecular recognition of folic acid by folate receptors,” can be found at:


About Van Andel Institute

Established by Jay and Betty Van Andel in 1996, Van Andel Institute (VAI) is an independent research and educational organization based in Grand Rapids, Mich., dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process.  Van Andel Research Institute (VARI), VAI’s research arm, is dedicated to studying the genetic, cellular and molecular origins of cancer, Parkinson’s and other diseases and working to translate those findings into effective therapies. This is accomplished through the work of more than 200 researchers in on-site laboratories and in collaborative partnerships that span the globe. Find out more about Van Andel Institute or donate by visiting www.vai.or