Structure Basis for Molecular Recognition of Folic Acid by Folate Receptor

Abstract

Folates are one-carbon donors that are required for the synthesis of nucleic acids. Rapidly dividing cells, such as cancer cells, are therefore much more dependent on folates than quiescent body cells. FRs are cell surface glycoproteins that mediate high affinity folate uptake through endocytosis. FRs are significantly expressed only in few cells to allow selective folate uptake under folate-limiting conditions. A large proportion of tumors therefore hijack FR and express it at very high levels to meet their folate demand. High level expression of folate receptor is so cancer-specific that it is hotly pursued as an anticancer drug target. In this study, we have successfully solved the long awaited crystal structure of FRa bound to folic acid. This structure provided a detailed map of the extensive interaction network between folic acid and FRs, and rationalizes previous structure-activity relationship studies. The information uncovered in this study paves the way for future structure-based rational drug design of more specific FR-targeted therapeutics.