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PDBsum entry 4kmx
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Membrane protein
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PDB id
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4kmx
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References listed in PDB file
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Key reference
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Title
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Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition.
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Authors
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A.S.Wibowo,
M.Singh,
K.M.Reeder,
J.J.Carter,
A.R.Kovach,
W.Meng,
M.Ratnam,
F.Zhang,
C.E.Dann.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
15180-15188.
[DOI no: ]
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PubMed id
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Abstract
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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.
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