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[[Image:1dls.png|left|200px]]


{{STRUCTURE_1dls|  PDB=1dls  |  SCENE=  }}
==METHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERS==
 
<StructureSection load='1dls' size='340' side='right'caption='[[1dls]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
===METHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERS===
== Structural highlights ==
 
<table><tr><td colspan='2'>[[1dls]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The October 2002 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Dihydrofolate Reductase''  by David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2002_10 10.2210/rcsb_pdb/mom_2002_10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DLS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DLS FirstGlance]. <br>
{{ABSTRACT_PUBMED_7890613}}
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
 
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
==About this Structure==
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1dls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dls OCA], [https://pdbe.org/1dls PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dls RCSB], [https://www.ebi.ac.uk/pdbsum/1dls PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dls ProSAT]</span></td></tr>
[[1dls]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The October 2002 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Dihydrofolate Reductase''  by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2002_10 10.2210/rcsb_pdb/mom_2002_10]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DLS OCA].  
</table>
== 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/dl/1dls_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=1dls ConSurf].
<div style="clear:both"></div>


==See Also==
==See Also==
*[[Dihydrofolate reductase|Dihydrofolate reductase]]
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:007890613</ref><references group="xtra"/>
__TOC__
</StructureSection>
[[Category: Dihydrofolate Reductase]]
[[Category: Dihydrofolate Reductase]]
[[Category: Dihydrofolate reductase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: Cody, V.]]
[[Category: Cody V]]
[[Category: Galitsky, N.]]
[[Category: Galitsky N]]
[[Category: Luft, J R.]]
[[Category: Luft JR]]
[[Category: Pangborn, W.]]
[[Category: Pangborn W]]
[[Category: Oxido-reductase]]

Latest revision as of 09:55, 7 February 2024

METHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERSMETHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERS

Structural highlights

1dls is a 1 chain structure with sequence from Homo sapiens. The October 2002 RCSB PDB Molecule of the Month feature on Dihydrofolate Reductase by David S. Goodsell is 10.2210/rcsb_pdb/mom_2002_10. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DYR_HUMAN Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM: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.[1] [2]

Function

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.[3] [4]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet. 2011 Feb 11;88(2):216-25. doi: 10.1016/j.ajhg.2011.01.004. PMID:21310276 doi:10.1016/j.ajhg.2011.01.004
  2. ↑ Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011 Feb 11;88(2):226-31. doi: 10.1016/j.ajhg.2011.01.007. PMID:21310277 doi:10.1016/j.ajhg.2011.01.007
  3. ↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
  4. ↑ Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW. Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol. 2002 Jul 12;320(3):677-93. PMID:12096917

1dls, resolution 2.30Å

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