Structural basis for molecular recognition of folic acid by folate receptors

Abstract

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 conditions1–3. 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 toxins6–8. 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.

In vivo evaluation of riboflavin receptor targeted fluorescent USPIO in mice with prostate cancer xenografts

“…In this context, a rapid translocation of the vitamin-tagged cargo into cancer cells was observed via receptor-mediated endocytosis, e.g. for folic acid-and riboflavin (Rf)-tagged agents [6][7][8][9][10][11][12]. In this study, we focused on Rf, an essential vitamin that mediates various biochemical, physiological, and metabolic (e.g.…”

Polymeric nanoparticles for optical sensing

“…SNPs with magnetic cores and fluorescent shells were used for imaging of cancer tissues due to specific binding of the particles with the folate receptor, which is up-regulated in several human cancers, allowing enhanced tumor targeting capability (Sudimack and Lee, 2000). Very recently, it has been investigated how folic acid binds to its receptors, whose crystal structure was also determined (Chen et al, 2013). These findings can provide a rationale for the design of drugs specifically targeted for the folate receptors.…”

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

“…The xenobiotics of this category associate into the FAR hydrophobic core while concomitantly associating with the hydrophilic exterior FAR cationic (+) R groups via the carboxyl (COO -) groups (107), which results in a contraction-pull down of the loose non-aligned multi-α-helix FAR towards the CM. This results in the endocytosis of the ligand-FAR complex at a much faster rate than that induced by endogenous ligand folic acid (folate), which has a lower kDa than that of the competitive pro-endocytic xenobiotics of this category (108) (Table VIII and Fig.…”