Title : 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 conditions
- The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti- FRα antibodies, high-affinity antifolates, folate-based imaging agents and folate-conjugated drugs and toxins
- 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
Output (sent_index, trigger,
protein,
sugar,
site):
- 1. glycoproteins, , Folate receptors (FRα, FRβ and FRγ), -, -
- 1. glycoproteins, , glycoproteins, -, -
Output(Part-Of) (sent_index,
protein,
site):
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):