4KN0

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

Summary for 4KN0

• Entry DOI: 10.2210/pdb4kn0/pdb
• Related: 4KM6 4KM7 4KMX 4KMY 4KMZ 4KN1 4KN2
• Descriptor: Folate receptor beta, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, METHOTREXATE, ... (6 entities in total)
• Functional Keywords: folate receptor beta, folr2, folate receptor, folic acid, folates, 5-methyltetrahydrofolate, antifolates, folate-conjugates, gpi-anchored protein on eukaryotic membrane, transport protein, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 25435.23

Authors

Wibowo, A.S.,Dann III, C.E. (deposition date: 2013-05-08, release date: 2013-08-07, Last modification date: 2024-11-20)

Primary citation

Wibowo, A.S.,Singh, M.,Reeder, K.M.,Carter, J.J.,Kovach, A.R.,Meng, W.,Ratnam, M.,Zhang, F.,Dann, C.E.
Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition.
Proc.Natl.Acad.Sci.USA, 110:15180-15188, 2013

PubMed 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.

PubMed: 23934049
DOI: 10.1073/pnas.1308827110

Experimental method

X-RAY DIFFRACTION (2.1 Å)