1s3y

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[[Image:1s3y.jpg|left|200px]]<br /><applet load="1s3y" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1s3y, resolution 2.25&Aring;" />
 
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'''Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry'''<br />
 
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==Overview==
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==Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry==
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Structural data are reported for the first examples of the tetrahydroquinazoline antifolate (6R,6S)-2,4-diamino-6-(1-indolinomethyl)-5,6,7,8-tetrahydroquinazoline (1) and its trimethoxy analogue (6R,6S)-2,4-diamino-6-(3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydroquinaz oline (2) as inhibitor complexes with dihydrofolate reductase (DHFR) from human (hDHFR) and Pneumocystis carinii (pcDHFR) sources. The indoline analogue (1) was crystallized as ternary complexes with NADPH and hDHFR (1.9 A resolution) and pcDHFR (2.3 A resolution), while the trimethoxy quinazoline analogue (2) was crystallized as a binary complex with hDHFR in two polymorphic rhombohedral R3 lattices: R3(1) to 1.8 A resolution and R3(2) to 2.0 A resolution. Structural analysis of these potent and selective DHFR-inhibitor complexes revealed preferential binding of the 6S-equatorial isomer in each structure. This configuration is similar to that of the natural tetrahydrofolate substrate; that is, 6S. These data also show that in both the hDHFR and pcDHFR ternary complexes with (1) the indoline ring is partially disordered, with two static conformations that differ between structures. These conformers also differ from that observed for the trimethoxybenzyl ring of tetrahydroquinazoline (2). There is also a correlation between the disorder of the flexible loop 23 and the disorder of the cofactor nicotinamide ribose ring in the pcDHFR-NADPH-(1) ternary complex. Comparison of the Toxoplasma gondii DHFR (tgDHFR) sequence with those of other DHFRs provides insight into the role of sequence and conformation in inhibitor-binding preferences which may aid in the design of novel antifolates with specific DHFR selectivity.
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<StructureSection load='1s3y' size='340' side='right'caption='[[1s3y]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1s3y]] 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=1S3Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1S3Y 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]] 2.25&#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=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=TQT:6-(OCTAHYDRO-1H-INDOL-1-YLMETHYL)DECAHYDROQUINAZOLINE-2,4-DIAMINE'>TQT</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=1s3y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1s3y OCA], [https://pdbe.org/1s3y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1s3y RCSB], [https://www.ebi.ac.uk/pdbsum/1s3y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1s3y 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/s3/1s3y_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=1s3y 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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1S3Y 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=TQT:'>TQT</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=1S3Y 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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Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry., Cody V, Luft JR, Pangborn W, Gangjee A, Queener SF, Acta Crystallogr D Biol Crystallogr. 2004 Apr;60(Pt 4):646-55. Epub 2004, Mar 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15039552 15039552]
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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: 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: NAP]]
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[[Category: TQT]]
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[[Category: inhibitors]]
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[[Category: pneumocystis carinii dihydrofolate reductase]]
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[[Category: stereochemistry]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:57:40 2008''
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Current revision

Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry

PDB ID 1s3y

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