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[[Image:1hfq.gif|left|200px]]


{{Structure
==COMPARISON OF TERNARY CRYSTAL COMPLEXES OF HUMAN DIHYDROFOLATE REDUCTASE WITH NADPH AND A CLASSICAL ANTITUMOR FUROPYRIMDINE==
|PDB= 1hfq |SIZE=350|CAPTION= <scene name='initialview01'>1hfq</scene>, resolution 2.1&Aring;
<StructureSection load='1hfq' size='340' side='right'caption='[[1hfq]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=MOT:N-[4-[(2,4-DIAMINOFURO[2,3D]PYRIMIDIN-5-YL)METHYL]METHYLAMINO]-BENZOYL]-L-GLUTAMATE'>MOT</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>
<table><tr><td colspan='2'>[[1hfq]] 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=1HFQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HFQ FirstGlance]. <br>
|ACTIVITY= <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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
|GENE= POTENTIAL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MOT:N-[4-[(2,4-DIAMINOFURO[2,3D]PYRIMIDIN-5-YL)METHYL]METHYLAMINO]-BENZOYL]-L-GLUTAMATE'>MOT</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1hfq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hfq OCA], [https://pdbe.org/1hfq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hfq RCSB], [https://www.ebi.ac.uk/pdbsum/1hfq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hfq ProSAT]</span></td></tr>
|RELATEDENTRY=
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1hfq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hfq OCA], [http://www.ebi.ac.uk/pdbsum/1hfq PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1hfq RCSB]</span>
== Disease ==
}}
[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 ==
[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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hf/1hfq_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=1hfq ConSurf].
<div style="clear:both"></div>


'''COMPARISON OF TERNARY CRYSTAL COMPLEXES OF HUMAN DIHYDROFOLATE REDUCTASE WITH NADPH AND A CLASSICAL ANTITUMOR FUROPYRIMDINE'''
==See Also==
 
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
 
== References ==
==Overview==
<references/>
The novel furopyrimidine, N-[4-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-methyl]-methylamino] -benzoyl]-L-glutamate (MTXO), a classical antifolate with weak antitumor activity compared with methotrexate (MTX), has been studied as inhibitorcofactor ternary crystal complexes with recombinant Phe-31 to Ser (F31S) and Phe-31 to Gly (F31G) variant human dihydrofolate reductase (hDHFR). Kinetic data show that the binding affinity of MTXO is significantly weaker for the variant hDHFR enzyme than for the wild type enzyme. Structural data for the Phe-31 variants, along with wild type hDHFR, provide the first direct comparison of the binding interactions of a single antifolate in a family of variant hDHFR. These ternary hDHFR complexes crystallize in the rhombohedral space group R3, isomorphous to that reported for wild type hDHFR MTXO-NADPH ternary complex. MTXO binds with its 2,4-diaminofuropyrimidine ring interacting with Glu-30 in hDHFR. The greatest change on modification of the side chain at position 31 is loss of hydrophobic contacts to the inhibitor, which results in the significant decrease in binding affinity of MTXO for the Phe-31 variants. The presence of the 6-5 furopyrimidine ring instead of the 6-6 pteridine ring causes a different bridge conformation compared with MTX, and in the case of the wild type MTXO complex also results in weaker hydrophobic contacts to Phe-31 than observed for MTXT. For the design of antitumor agents related to MTXO, increasing the bridge of MTXO from two to three or four atoms should provide increased DHFR inhibitory potency and antitumor activity.
__TOC__
 
</StructureSection>
==About this Structure==
1HFQ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HFQ OCA].
 
==Reference==
Comparison of ternary crystal complexes of F31 variants of human dihydrofolate reductase with NADPH and a classical antitumor furopyrimidine., Cody V, Galitsky N, Luft JR, Pangborn W, Blakley RL, Gangjee A, Anticancer Drug Des. 1998 Jun;13(4):307-15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9627670 9627670]
[[Category: Dihydrofolate reductase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Blakley, R L.]]
[[Category: Blakley RL]]
[[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.]]
[[Category: Pangborn W]]
[[Category: one-carbon metabolism]]
[[Category: oxidoreductase]]
 
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