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| | ==Human folate receptor alpha (FOLR1) at acidic pH, hexagonal form== | | ==Human folate receptor alpha (FOLR1) at acidic pH, hexagonal form== |
| - | <StructureSection load='4kmx' size='340' side='right' caption='[[4kmx]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='4kmx' size='340' side='right'caption='[[4kmx]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4kmx]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KMX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KMX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4kmx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KMX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4km6|4km6]], [[4km7|4km7]], [[4kmy|4kmy]], [[4kmz|4kmz]], [[4kn0|4kn0]], [[4kn1|4kn1]], [[4kn2|4kn2]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4kmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kmx OCA], [https://pdbe.org/4kmx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kmx RCSB], [https://www.ebi.ac.uk/pdbsum/4kmx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kmx ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4kmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kmx OCA], [http://pdbe.org/4kmx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4kmx RCSB], [http://www.ebi.ac.uk/pdbsum/4kmx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4kmx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/FOLR1_HUMAN FOLR1_HUMAN]] Neurodegenerative syndrome due to cerebral folate transport deficiency. Neurodegeneration due to cerebral folate transport deficiency (NCFTD) [MIM:[http://omim.org/entry/613068 613068]]: A neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy. Note=The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/FOLR1_HUMAN FOLR1_HUMAN] Neurodegenerative syndrome due to cerebral folate transport deficiency. Neurodegeneration due to cerebral folate transport deficiency (NCFTD) [MIM:[https://omim.org/entry/613068 613068]: A neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy. Note=The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FOLR1_HUMAN FOLR1_HUMAN]] Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells. | + | [https://www.uniprot.org/uniprot/FOLR1_HUMAN FOLR1_HUMAN] Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: III, C E.Dann]] | + | [[Category: Large Structures]] |
| - | [[Category: Wibowo, A S]] | + | [[Category: Dann III CE]] |
| - | [[Category: 5-methyltetrahydrofolate]] | + | [[Category: Wibowo AS]] |
| - | [[Category: Antifolate]]
| + | |
| - | [[Category: Folate receptor]]
| + | |
| - | [[Category: Folate receptor alpha]]
| + | |
| - | [[Category: Folate-conjugate]]
| + | |
| - | [[Category: Folate]]
| + | |
| - | [[Category: Folic acid]]
| + | |
| - | [[Category: Folr1]]
| + | |
| - | [[Category: Gpi-anchored protein on eukaryotic membrane]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| Structural highlights
Disease
FOLR1_HUMAN Neurodegenerative syndrome due to cerebral folate transport deficiency. Neurodegeneration due to cerebral folate transport deficiency (NCFTD) [MIM:613068: A neurodegenerative disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy and leukodystrophy. Note=The disease is caused by mutations affecting the gene represented in this entry.
Function
FOLR1_HUMAN Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells.
Publication Abstract from PubMed
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.
Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition.,Wibowo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W, Ratnam M, Zhang F, Dann CE 3rd Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15180-8. doi:, 10.1073/pnas.1308827110. Epub 2013 Aug 9. PMID:23934049[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wibowo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W, Ratnam M, Zhang F, Dann CE 3rd. Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15180-8. doi:, 10.1073/pnas.1308827110. Epub 2013 Aug 9. PMID:23934049 doi:10.1073/pnas.1308827110
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