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1daj

From Proteopedia

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[[Image:1daj.gif|left|200px]]<br />
 
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<applet load="1daj" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1daj, resolution 2.30&Aring;" />
 
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'''COMPARISON OF TERNARY COMPLEXES OF PNEUMOCYSTIS CARINII AND WILD TYPE HUMAN DIHYDROFOLATE REDUCTASE WITH COENZYME NADPH AND A NOVEL CLASSICAL ANTITUMOR FURO[2,3D]PYRIMIDINE ANTIFOLATE'''<br />
 
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==Overview==
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==COMPARISON OF TERNARY COMPLEXES OF PNEUMOCYSTIS CARINII AND WILD TYPE HUMAN DIHYDROFOLATE REDUCTASE WITH COENZYME NADPH AND A NOVEL CLASSICAL ANTITUMOR FURO[2,3D]PYRIMIDINE ANTIFOLATE==
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The novel furopyrimidine, N-(4-{N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]methylamino}benzoyl), -L- glutamate (MTXO), a classical antifolate with antitumor activity, comparable to that of methotrexate (MTX), has been studied as, inhibitor-cofactor ternary crystal complexes with wild-type Pneumocystis, carinii (pc) and recombinant human wild-type dihydrofolate reductase, (hDHFR). These structural data provide the first direct comparison of the, binding interactions of the same antifolate inhibitor in the active site, for pc and human DHFR. The human ternary DHFR complex crystallizes in the, rhombohedral space group R3 and is isomorphous to the ternary complex, reported for a gamma-tetrazole methotrexate analogue, MTXT. The pcDHFR, complex crystallizes in the monoclinic space group P2(1) and is, isomorphous to that reported for a trimethoprim (TMP) complex., Interpretation of difference Fourier electron-density maps for these, ternary complexes revealed that MTXO binds with its, 2,4-diaminofuropyrimidine ring interacting with Glu32 in pc and Glu30 in, human DHFR, as observed for MTXT. The presence of the 6-5 furopyrimidine, ring instead of the 6-6 pteridine ring results in a different bridge, conformation compared with that of MTXT. The bridge torsion angles for, MTXO, i.e. C(4a)-C(5)-C(8)-N(9) and C(5)-C(8)-N(9)-C(1'), are -156.5/51.9, degrees and -162.6/51.8 degrees, respectively for h and pc, compared with, -146.8/57.4 degrees for MTXT. In each case, the p-aminobenzoylglutamate, conformation is similar to that observed for MTXT. In the pcDHFR complex, the active-site region is conserved and the additional 20 residues in the, sequence compared with the human enzyme are located in external loop, regions. There is a significant change in the nicotinamide ribose, conformation of the cofactor which places the nicotinamide O atom close to, the 4NH(2) group of MTXO (2.7 A), a shift not observed in hDHFR, structures. As a consequence of this, there is a loss of a hydrogen bond, between the nicotinamide carbonyl group and the backbone of Ala12 in, pcDHFR. In the human ternary complexes, the cofactor NADPH is bound with a, more extended conformation, and the nicotinamide O atom makes a 3.5 A, contact with the 4NH(2) group of MTXO. Although the novel classical, antifolate MTXO is not highly active against pcDHFR, there are, correlations between its binding interactions consistent with its lower, potency as an inhibitor of h and pcDHFR compared with MTX.
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<StructureSection load='1daj' size='340' side='right'caption='[[1daj]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1daj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DAJ 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]] 2.3&#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=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>
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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=1daj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1daj OCA], [https://pdbe.org/1daj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1daj RCSB], [https://www.ebi.ac.uk/pdbsum/1daj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1daj ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DYR_PNECA DYR_PNECA] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
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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/da/1daj_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=1daj 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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1DAJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii] with NDP and MOT 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] Structure known Active Site: S1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1DAJ 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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Comparison of ternary complexes of Pneumocystis carinii and wild-type human dihydrofolate reductase with coenzyme NADPH and a novel classical antitumor furo[2,3-d]pyrimidine antifolate., Cody V, Galitsky N, Luft JR, Pangborn W, Gangjee A, Devraj R, Queener SF, Blakley RL, Acta Crystallogr D Biol Crystallogr. 1997 Nov 1;53(Pt 6):638-49. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15299851 15299851]
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[[Category: Large Structures]]
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[[Category: Dihydrofolate reductase]]
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[[Category: Pneumocystis carinii]]
[[Category: Pneumocystis carinii]]
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[[Category: Single protein]]
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[[Category: Blakley RL]]
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[[Category: Blakley, R.L.]]
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[[Category: Cody V]]
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[[Category: Cody, V.]]
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[[Category: Devraj R]]
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[[Category: Devraj, R.]]
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[[Category: Galitsky N]]
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[[Category: Galitsky, N.]]
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[[Category: Gangjee A]]
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[[Category: Gangjee, A.]]
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[[Category: Luft JR]]
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[[Category: Luft, J.R.]]
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[[Category: Pangborn W]]
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[[Category: Pangborn, W.]]
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[[Category: Queener SF]]
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[[Category: Queener, S.F.]]
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[[Category: MOT]]
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[[Category: NDP]]
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[[Category: oxidoreductase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:58:04 2007''
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Current revision

COMPARISON OF TERNARY COMPLEXES OF PNEUMOCYSTIS CARINII AND WILD TYPE HUMAN DIHYDROFOLATE REDUCTASE WITH COENZYME NADPH AND A NOVEL CLASSICAL ANTITUMOR FURO[2,3D]PYRIMIDINE ANTIFOLATE

PDB ID 1daj

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