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<StructureSection load='1mvs' size='340' side='right'caption='[[1mvs]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
<StructureSection load='1mvs' size='340' side='right'caption='[[1mvs]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1mvs]] 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=1MVS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1MVS FirstGlance]. <br>
<table><tr><td colspan='2'>[[1mvs]] 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=1MVS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1MVS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DTM:2,4-DIAMINO-6-[N-(3,4,5-TRIMETHOXYBENZYL)-N-METHYLAMINO]PYRIDO[2,3-D]PYRIMIDINE'>DTM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.9&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ly3|1ly3]], [[1ly4|1ly4]], [[1mvt|1mvt]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DTM:2,4-DIAMINO-6-[N-(3,4,5-TRIMETHOXYBENZYL)-N-METHYLAMINO]PYRIDO[2,3-D]PYRIMIDINE'>DTM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=1mvs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mvs OCA], [https://pdbe.org/1mvs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1mvs RCSB], [https://www.ebi.ac.uk/pdbsum/1mvs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1mvs 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=1mvs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mvs OCA], [http://pdbe.org/1mvs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1mvs RCSB], [http://www.ebi.ac.uk/pdbsum/1mvs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1mvs ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[http://omim.org/entry/613839 613839]]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>
[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>
[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1mvs ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1mvs ConSurf].
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<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The results of the crystal structure determination of human dihydrofolate reductase (hDHFR) as a binary complex with the potent N9-C10 reversed-bridge antifolate inhibitor 2,4-diamino-6-[N-(3',4',5'-trimethoxybenzyl)-N-methylamino]pyrido[2,3-d]py rimidine (1) are reported for two independent polymorphic rhombohedral R3 lattices [R3(1) and R3(2)]. Data from these two crystal forms were refined to 1.90 A resolution for complex R3(1), with R = 0.186 for 9689 data, and to 1.80 A resolution for complex R3(2), with R = 0.194 for 13 305 data. Changes in the loop geometry between the two structures reflects contact differences in the packing environments in the two R3 lattices. The largest changes (between 0.5 and 1.7 A) are observed for the loop regions encompassing residues 16-25, 40-48, 81-89, 99-108, 143-148 and 161-169. Comparison of the intermolecular contacts of these loops reveals that the R3(2) lattice is more tightly packed, as reflected in its smaller V(M) value and smaller solvent content. The conformation of inhibitor (1) is similar in both structures and the N9-C10 bridge geometry is more similar to that observed for the normal C9-N10 bridge of trimetrexate (TMQ) than to the other N9-C10 reversed-bridge antifolates previously reported. The effect of the N9-C10 reversed-bridge geometry is to distort the bridge from coplanarity with the pyrido[2,3-d]pyrimidine ring system and to twist the C10 methylene conformation towards a gauche conformation. This also influences the conformation of the methoxybenzyl ring, moving it away from a trans position and placing the 5'-methoxy group deeper within the hydrophobic pocket made by Leu60, Pro61 and Asn64 of the hDHFR active site.
Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase.,Cody V, Galitsky N, Luft JR, Pangborn W, Gangjee A Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):654-61. Epub 2003, Mar 25. PMID:12657784<ref>PMID:12657784</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1mvs" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Dihydrofolate reductase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Cody, V]]
[[Category: Cody V]]
[[Category: Galitsky, N]]
[[Category: Galitsky N]]
[[Category: Gangjee, A]]
[[Category: Gangjee A]]
[[Category: Luft, J R]]
[[Category: Luft JR]]
[[Category: Pangborn, W A]]
[[Category: Pangborn WA]]
[[Category: Antifolate]]
[[Category: Human dhfr]]
[[Category: N9-c10 reverse bridge pyrolopyrimidine]]
[[Category: Oxidoreductase]]
Retrieved from "https://proteopedia.org/1mvs"