4KN0: Human folate receptor beta (FOLR2) in complex with the antifolate methotrexate

Citation:
Abstract
Antifolates, folate analogs that inhibit vitamin B9 (folic acid)-using cellular enzymes, have been used over several decades for the treatment of cancer and inflammatory diseases. Cellular uptake of the antifolates in clinical use occurs primarily via widely expressed facilitative membrane transporters. More recently, human folate receptors (FRs), high affinity receptors that transport folate via endocytosis, have been proposed as targets for the specific delivery of new classes of antifolates or folate conjugates to tumors or sites of inflammation. The development of specific, FR-targeted antifolates would be accelerated if additional biophysical data, particularly structural models of the receptors, were available. Here we describe six distinct crystallographic models that provide insight into biological trafficking of FRs and distinct binding modes of folate and antifolates to these receptors. From comparison of the structures, we delineate discrete structural conformations representative of key stages in the endocytic trafficking of FRs and propose models for pH-dependent conformational changes. Additionally, we describe the molecular details of human FR in complex with three clinically prevalent antifolates, pemetrexed (also Alimta), aminopterin, and methotrexate. On the whole, our data form the basis for rapid design and implementation of unique, FR-targeted, folate-based drugs for the treatment of cancer and inflammatory diseases.
PDB ID: 4KN0Download
MMDB ID: 112491
PDB Deposition Date: 2013/5/8
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4KN0: monomeric; determined by author and by software (PISA)
Molecular Components in 4KN0
Label Count Molecule
Protein (1 molecule)
1
Folate Receptor Beta(Gene symbol: FOLR2)
Molecule annotation
Chemicals (8 molecules)
1
1
2
1
3
2
4
4
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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