1u70

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[[Image:1u70.gif|left|200px]]<br /><applet load="1u70" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1u70, resolution 2.5&Aring;" />
 
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'''Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase'''<br />
 
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==Overview==
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==Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase==
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Structural data are reported to 2.5 A resolution for the first full analysis of the methotrexate-resistant Leu22Arg (L22R) variant of mouse dihydrofolate reductase (mDHFR) crystallized as a ternary complex with methotrexate (MTX) and the cofactor NADPH. These results are compared with the MTX and NADPH ternary complexes of L22R human DHFR (hDHFR) and those of mouse and human wild-type DHFR enzymes. The conformation of mDHFR Arg22 is such that it makes hydrogen-bonding contacts with Asp21, Trp24 and a structural water molecule, observations which were not made in the L22R hDHFR ternary complex. These data show that there is little difference between the structures of the wild type and L22R variant for either mouse or human DHFR; however, there are significant differences between the species. Comparison of these structures reveals that the active site of mDHFR is larger than that in the hDHFR structure. In mDHFR, the position of MTX is shifted 0.6 A toward helix C (residues 59-65), which in turn is shifted 1.2 A away from the active site relative to that observed in the hDHFR ternary complexes. In the L22R variant mDHFR structure, MTX makes shorter contacts to the conserved residues Ile7, Val115 and Tyr121 than in the L22R variant human DHFR structure. These contacts are comparable in both wild-type enzymes. The unexpected results from this comparison of the mouse and human DHFR complexes bound with the same ligand and cofactor illustrate the importance of detailed study of several species of enzyme, even when there is a high sequence homology between them. These data suggest that the differences in binding interactions of the L22R variant are in agreement with the weaker binding affinity for MTX in the variant enzymes; the larger size of the binding site in mDHFR supports the observation that the binding affinity of MTX for L22R mDHFR is significantly weaker than that of the L22R hDHFR enzyme.
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<StructureSection load='1u70' size='340' side='right'caption='[[1u70]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1u70]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U70 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1U70 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1u70 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u70 OCA], [https://pdbe.org/1u70 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1u70 RCSB], [https://www.ebi.ac.uk/pdbsum/1u70 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1u70 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DYR_MOUSE DYR_MOUSE] 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.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u7/1u70_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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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=1u70 ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1U70 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=MTX:'>MTX</scene> and <scene name='pdbligand=NDP:'>NDP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U70 OCA].
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH., Cody V, Luft JR, Pangborn W, Acta Crystallogr D Biol Crystallogr. 2005 Feb;61(Pt 2):147-55. Epub 2005, Jan 19. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15681865 15681865]
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[[Category: Large Structures]]
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[[Category: Dihydrofolate reductase]]
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[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Single protein]]
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[[Category: Cody V]]
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[[Category: Cody, V.]]
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[[Category: MTX]]
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[[Category: NDP]]
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[[Category: human]]
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[[Category: variant dhfr mouse]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:21:14 2008''
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Current revision

Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase

PDB ID 1u70

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