1ly3: Difference between revisions

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-[[Image:1ly3.gif|left|200px]]
- {{Structure
+==ANALYSIS OF QUINAZOLINE AND PYRIDOPYRIMIDINE N9-C10 REVERSED BRIDGE ANTIFOLATES IN COMPLEX WITH NADP+ AND PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE==
-|PDB= 1ly3 |SIZE=350|CAPTION= <scene name='initialview01'>1ly3</scene>, resolution 1.90&Aring;
+<StructureSection load='1ly3' size='340' side='right'caption='[[1ly3]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
-|SITE=
+== Structural highlights ==
-|LIGAND= <scene name='pdbligand=COG:2,4-DIAMINO-6-[N-(2&#39;,5&#39;-DIMETHOXYBENZYL)-N-METHYLAMINO]QUINAZOLINE'>COG</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>
+<table><tr><td colspan='2'>[[1ly3]] 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=1LY3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LY3 FirstGlance]. <br>
-|ACTIVITY= <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><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
-|GENE=
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=COG:2,4-DIAMINO-6-[N-(2,5-DIMETHOXYBENZYL)-N-METHYLAMINO]QUINAZOLINE'>COG</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
-|DOMAIN=
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ly3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ly3 OCA], [https://pdbe.org/1ly3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ly3 RCSB], [https://www.ebi.ac.uk/pdbsum/1ly3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ly3 ProSAT]</span></td></tr>
-|RELATEDENTRY=[[1ly4|1LY4]]
+</table>
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ly3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ly3 OCA], [http://www.ebi.ac.uk/pdbsum/1ly3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1ly3 RCSB]</span>
+== Function ==
-}}
+[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.
+== 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/ly/1ly3_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=1ly3 ConSurf].
+<div style="clear:both"></div>
-'''ANALYSIS OF QUINAZOLINE AND PYRIDOPYRIMIDINE N9-C10 REVERSED BRIDGE ANTIFOLATES IN COMPLEX WITH NADP+ AND PNEUMOCYSTIS CARINII DIHYDROFOLATE REDUCTASE'''
+==See Also==
+*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
+__TOC__
-==Overview==
+</StructureSection>
-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.
+[[Category: Large Structures]]
-==About this Structure==
-LY3 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Pneumocystis_carinii Pneumocystis carinii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LY3 OCA].
-==Reference==
-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://www.ncbi.nlm.nih.gov/pubmed/12198294 12198294]
-[[Category: Dihydrofolate reductase]]
 [[Category: Pneumocystis carinii]]
-[[Category: Single protein]]
+[[Category: Cody V]]
-[[Category: Cody, V.]]
+[[Category: Galitsky N]]
-[[Category: Galitsky, N.]]
+[[Category: Gangjee A]]
-[[Category: Gangjee, A.]]
+[[Category: Luft JR]]
-[[Category: Luft, J R.]]
+[[Category: Pangborn W]]
-[[Category: Pangborn, W.]]
+[[Category: Queener SF]]
-[[Category: Queener, S F.]]
-[[Category: pcdhfr reversed bridge antifolate]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:08:47 2008''