3d80

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{{STRUCTURE_3d80| PDB=3d80 | SCENE= }}
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==Structural Analysis of a Holo Enzyme Complex of Mouse Dihydrofolate Reductase with NADPH and a Ternary Complex wtih the Potent and Selective Inhibitor 2,4-Diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine==
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===Structural Analysis of a Holo Enzyme Complex of Mouse Dihydrofolate Reductase with NADPH and a Ternary Complex wtih the Potent and Selective Inhibitor 2,4-Diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine===
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<StructureSection load='3d80' size='340' side='right' caption='[[3d80]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
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{{ABSTRACT_PUBMED_18703847}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3d80]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D80 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3D80 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=Q22:(4AS)-5-[(2,4-DIAMINOPTERIDIN-6-YL)METHYL]-4A,5-DIHYDRO-2H-DIBENZO[B,F]AZEPIN-8-OL'>Q22</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2fzj|2fzj]], [[3d7x|3d7x]], [[3d7y|3d7y]], [[3d84|3d84]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Dhfr ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>
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<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>
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<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=3d80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d80 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3d80 RCSB], [http://www.ebi.ac.uk/pdbsum/3d80 PDBsum]</span></td></tr>
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</table>
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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/d8/3d80_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/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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It has been shown that 2,4-diamino-6-arylmethylpteridines and 2,4-diamino-5-arylmethylpyrimidines containing an O-carboxylalkyloxy group in the aryl moiety are potent and selective inhibitors of the dihydrofolate reductase (DHFR) from opportunistic pathogens such as Pneumocystis carinii, the causative agent of Pneumocystis pneumonia in HIV/AIDS patients. In order to understand the structure-activity profile observed for a series of substituted dibenz[b,f]azepine antifolates, the crystal structures of mouse DHFR (mDHFR; a mammalian homologue) holo and ternary complexes with NADPH and the inhibitor 2,4-diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine were determined to 1.9 and 1.4 A resolution, respectively. Structural data for the ternary complex with the potent O-(3-carboxypropyl) inhibitor PT684 revealed no electron density for the O-carboxylalkyloxy side chain. The side chain was either cleaved or completely disordered. The electron density fitted the less potent hydroxyl compound PT684a. Additionally, cocrystallization of mDHFR with NADPH and the less potent 2'-(4-carboxybenzyl) inhibitor PT682 showed no electron density for the inhibitor and resulted in the first report of a holoenzyme complex despite several attempts at crystallization of a ternary complex. Modeling data of PT682 in the active site of mDHFR and P. carinii DHFR (pcDHFR) indicate that binding would require ligand-induced conformational changes to the enzyme for the inhibitor to fit into the active site or that the inhibitor side chain would have to adopt an alternative binding mode to that observed for other carboxyalkyloxy inhibitors. These data also show that the mDHFR complexes have a decreased active-site volume as reflected in the relative shift of helix C (residues 59-64) by 0.6 A compared with pcDHFR ternary complexes. These data are consistent with the greater inhibitory potency against pcDHFR.
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==Function==
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Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2,4-diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine.,Cody V, Pace J, Rosowsky A Acta Crystallogr D Biol Crystallogr. 2008 Sep;64(Pt 9):977-84. Epub 2008, Aug 13. PMID:18703847<ref>PMID:18703847</ref>
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[[http://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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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3d80]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D80 OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:018703847</ref><references group="xtra"/><references/>
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*[[Dihydrofolate reductase|Dihydrofolate reductase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Dihydrofolate reductase]]
[[Category: Dihydrofolate reductase]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Cody, V.]]
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[[Category: Cody, V]]
[[Category: Mouse holo enzyme ternary ligand complex dihydrofolate reductase]]
[[Category: Mouse holo enzyme ternary ligand complex dihydrofolate reductase]]
[[Category: Nadp]]
[[Category: Nadp]]
[[Category: One-carbon metabolism]]
[[Category: One-carbon metabolism]]
[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]

Revision as of 13:27, 18 December 2014

Structural Analysis of a Holo Enzyme Complex of Mouse Dihydrofolate Reductase with NADPH and a Ternary Complex wtih the Potent and Selective Inhibitor 2,4-Diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine

3d80, resolution 1.40Å

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