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| | <StructureSection load='5izq' size='340' side='right'caption='[[5izq]], [[Resolution|resolution]] 3.60Å' scene=''> | | <StructureSection load='5izq' size='340' side='right'caption='[[5izq]], [[Resolution|resolution]] 3.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5izq]] is a 8 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=5IZQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IZQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5izq]] is a 8 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=5IZQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IZQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=83A:N-(4-{[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-6-YL)ETHYL]AMINO}BENZENE-1-CARBONYL)-L-GLUTAMIC+ACID'>83A</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]] 3.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FOLR1, FOLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=83A:N-(4-{[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-6-YL)ETHYL]AMINO}BENZENE-1-CARBONYL)-L-GLUTAMIC+ACID'>83A</scene></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=5izq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5izq OCA], [http://pdbe.org/5izq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5izq RCSB], [http://www.ebi.ac.uk/pdbsum/5izq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5izq ProSAT]</span></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=5izq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5izq OCA], [https://pdbe.org/5izq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5izq RCSB], [https://www.ebi.ac.uk/pdbsum/5izq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5izq 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: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brunzelle, J S]] | + | [[Category: Brunzelle JS]] |
| - | [[Category: Gu, X]] | + | [[Category: Gu X]] |
| - | [[Category: Ke, J]] | + | [[Category: Ke J]] |
| - | [[Category: Melcher, K]] | + | [[Category: Melcher K]] |
| - | [[Category: Xu, H E]] | + | [[Category: Xu HE]] |
| - | [[Category: Antifolate]]
| + | |
| - | [[Category: Folate receptor alpha]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Tumor targeting]]
| + | |
| 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
Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) alpha and beta or the proton-coupled folate transporter. Results show increased in vitro anti-proliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analog 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRalpha and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRalpha and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents.
Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions Via Cellular Uptake by Folate Receptor alpha and the Proton-coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis.,Golani LK, Wallace-Povirk A, Deis SM, Wong JE, Ke J, Gu X, Raghavan S, Wilson MR, Li X, Polin LA, de Waal PW, White K, Kushner J, O'Connor CE, Hou Z, Xu HE, Melcher K, Dann Iii CE, Matherly LH, Gangjee A J Med Chem. 2016 Jul 26. PMID:27458733[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Golani LK, Wallace-Povirk A, Deis SM, Wong JE, Ke J, Gu X, Raghavan S, Wilson MR, Li X, Polin LA, de Waal PW, White K, Kushner J, O'Connor CE, Hou Z, Xu HE, Melcher K, Dann Iii CE, Matherly LH, Gangjee A. Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions Via Cellular Uptake by Folate Receptor alpha and the Proton-coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis. J Med Chem. 2016 Jul 26. PMID:27458733 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00594
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