1ia2: Difference between revisions
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New page: left|200px<br /><applet load="1ia2" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ia2, resolution 1.82Å" /> '''Candida albicans dih... |
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== | ==Candida albicans dihydrofolate reductase complexed with dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) and 5-[(4-METHYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW578)== | ||
X-ray crystallographic analysis of 5-(4'-substituted | <StructureSection load='1ia2' size='340' side='right'caption='[[1ia2]], [[Resolution|resolution]] 1.82Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1ia2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_albicans Candida albicans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1IA2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1IA2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.82Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=TQ4:5-[(4-METHYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE'>TQ4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1ia2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ia2 OCA], [https://pdbe.org/1ia2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ia2 RCSB], [https://www.ebi.ac.uk/pdbsum/1ia2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ia2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DYR_CANAX DYR_CANAX] 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/ia/1ia2_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=1ia2 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
X-ray crystallographic analysis of 5-(4'-substituted phenyl)sulfanyl-2,4-diaminoquinazoline inhibitors in ternary complex with Candida albicans dihydrofolate reductase (DHFR) and NADPH revealed two distinct modes of binding. The two compounds with small 4'-substituents (H and CH3) were found to bind with the phenyl group oriented in the plane of the quinazoline ring system and positioned adjacent to the C-helix. In contrast, the more selective inhibitors with larger 4'-substituents (tert-butyl and N-morpholino) were bound to the enzyme with the phenyl group perpendicular to the quinazoline ring and positioned in the region of the active site that typically binds the dihydronicotinamide moiety of NADPH. The cofactor appeared bound to DHFR but with the disordered dihydronicotinamide swung away from the protein surface and into solution. This unusual inhibitor binding mode may play an important role in the high DHFR selectivity of these compounds and also may provide new ideas for inhibitor design. | |||
X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor.,Whitlow M, Howard AJ, Stewart D, Hardman KD, Chan JH, Baccanari DP, Tansik RL, Hong JS, Kuyper LF J Med Chem. 2001 Aug 30;44(18):2928-32. PMID:11520201<ref>PMID:11520201</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
<div class="pdbe-citations 1ia2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Candida albicans]] | [[Category: Candida albicans]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Howard AJ]] | |||
[[Category: Howard | [[Category: Kuyper LF]] | ||
[[Category: Kuyper | [[Category: Whitlow M]] | ||
[[Category: Whitlow | |||
Latest revision as of 09:24, 9 August 2023
Candida albicans dihydrofolate reductase complexed with dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) and 5-[(4-METHYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW578)Candida albicans dihydrofolate reductase complexed with dihydro-nicotinamide-adenine-dinucleotide phosphate (NADPH) and 5-[(4-METHYLPHENYL)SULFANYL]-2,4-QUINAZOLINEDIAMINE (GW578)
Structural highlights
FunctionDYR_CANAX Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedX-ray crystallographic analysis of 5-(4'-substituted phenyl)sulfanyl-2,4-diaminoquinazoline inhibitors in ternary complex with Candida albicans dihydrofolate reductase (DHFR) and NADPH revealed two distinct modes of binding. The two compounds with small 4'-substituents (H and CH3) were found to bind with the phenyl group oriented in the plane of the quinazoline ring system and positioned adjacent to the C-helix. In contrast, the more selective inhibitors with larger 4'-substituents (tert-butyl and N-morpholino) were bound to the enzyme with the phenyl group perpendicular to the quinazoline ring and positioned in the region of the active site that typically binds the dihydronicotinamide moiety of NADPH. The cofactor appeared bound to DHFR but with the disordered dihydronicotinamide swung away from the protein surface and into solution. This unusual inhibitor binding mode may play an important role in the high DHFR selectivity of these compounds and also may provide new ideas for inhibitor design. X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor.,Whitlow M, Howard AJ, Stewart D, Hardman KD, Chan JH, Baccanari DP, Tansik RL, Hong JS, Kuyper LF J Med Chem. 2001 Aug 30;44(18):2928-32. PMID:11520201[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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