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1ly4

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[[Image:1ly4.gif|left|200px]]<br /><applet load="1ly4" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1ly4, resolution 2.1&Aring;" />
 
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'''Analysis of quinazoline and PYRIDO[2,3D]PYRIMIDINE N9-C10 reversed bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductase'''<br />
 
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==Overview==
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==Analysis of quinazoline and PYRIDO[2,3D]PYRIMIDINE N9-C10 reversed bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductase==
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Structural studies of two ternary complexes of Pneumocystis carinii dihydrofolate reductase (pcDHFR) with the cofactor NADP(+) and potent antifolates, the N9-C10 reversed-bridge inhibitor 2,4-diamino-6-[N-(2',5'-dimethoxybenzyl)-N-methylamino]quinazoline (1) and its 3',5'-dimethoxypyrido[2,3-d]pyrimidine analog (2), were carried out. Data for the monoclinic crystals were refined to 1.90 A resolution for the complex with (1) (R = 0.178) and to 2.1 A resolution for the complex with (2) (R = 0.193). The effect of the N9-C10 reversed-bridge geometry is to distort the bridge from coplanarity with the pyrido[2,3-d]pyrimidine or quinazoline ring system and to twist the C10 methylene conformation toward a gauche conformation. This change also influences the conformation of the methoxybenzyl ring, moving it away from a trans position. This change places the 5'-methoxy group deeper within the hydrophobic pocket made by Ile65, Pro66 and Phe69 of the pcDHFR active site. These results also revealed the first observation of an unusual conformation for the reversed-bridge geometry (C5-C6-N9-C10 torsion angle) in antifolate (2). The electron density is consistent with the presence of two models (conformers 2-1 and 2-2) that result from inversion of the geometry at N9. The four examples of N9-C10 reversed-bridge antifolates cluster in two conformations, with the structure of quinazoline (1) similar to that previously reported for its 2',5'-dimethoxypyrido[2,3-d]pyrimidine analog (3). The two conformers of (2) differ from these and each other by a twisted-bridge geometry that results in the dimethoxybenzyl ring occupying the same conformational space. Conformer 2-2 also has the N9-C10 reversed bridge perpendicular to the pyrido[2,3-d]pyrimidine plane, in contrast to the gauche-trans conformation normally observed. As a result of these changes, the N9 methyl probes conformational space in the active site not normally occupied by antifolate structures. The N9 methyl of conformer 2-2 makes close contacts to the conserved Leu25 as well as the hydroxyl O atoms of the nicotinamide ribose and Ser64, whereas the other three reversed-bridge conformers make weak hydrophobic contacts with Ile123, Thr61 and Ile65. These antifolates are ten times more selective for pcDHFR than the C9-N10 bridge parent trimetrexate. However, pyrido[2,3-d]pyrimidines (2) and (3) are three times more selective for pcDHFR than quinazoline (1) is for rat liver DHFR. These data suggest that the loss of hydrogen-bonding interactions with N8 is more important to potency than the interactions of the methoxybenzyl substituents.
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<StructureSection load='1ly4' size='340' side='right'caption='[[1ly4]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1ly4]] 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=1LY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LY4 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]] 2.1&#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=COQ:2,4-DIAMINO-6-[N-(3,5-DIMETHOXYBENZYL)-N-METHYLAMINO]PYRIDO[2,3-D]PYRIMIDINE'>COQ</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=1ly4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ly4 OCA], [https://pdbe.org/1ly4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ly4 RCSB], [https://www.ebi.ac.uk/pdbsum/1ly4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ly4 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/ly/1ly4_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=1ly4 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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1LY4 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 <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=COQ:'>COQ</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=1LY4 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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Analysis of quinazoline and pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductase., Cody V, Galitsky N, Luft JR, Pangborn W, Queener SF, Gangjee A, Acta Crystallogr D Biol Crystallogr. 2002 Sep;58(Pt 9):1393-9. Epub 2002, Aug 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12198294 12198294]
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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: Cody V]]
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[[Category: Cody, V.]]
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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: COQ]]
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[[Category: NAP]]
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[[Category: n9-c10 reversed bridge pyridopyrimidine antifolate]]
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[[Category: pcdhfr]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:49:45 2008''
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Current revision

Analysis of quinazoline and PYRIDO[2,3D]PYRIMIDINE N9-C10 reversed bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductase

PDB ID 1ly4

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