1aoe: Difference between revisions
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< | ==CANDIDA ALBICANS DIHYDROFOLATE REDUCTASE COMPLEXED WITH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NADPH) AND 1,3-DIAMINO-7-(1-ETHYEPROPYE)-7H-PYRRALO-[3,2-F]QUINAZOLINE (GW345)== | ||
<StructureSection load='1aoe' size='340' side='right'caption='[[1aoe]], [[Resolution|resolution]] 1.60Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[1aoe]] 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=1AOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1AOE 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]] 1.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GW3:7-(1-ETHYL-PROPYL)-7H-PYRROLO-[3,2-F]QUINAZOLINE-1,3-DIAMINE'>GW3</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=1aoe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1aoe OCA], [https://pdbe.org/1aoe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1aoe RCSB], [https://www.ebi.ac.uk/pdbsum/1aoe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1aoe 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/ao/1aoe_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=1aoe ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The recent rise in systemic fungal infections has created a need for the development of new antifungal agents. As part of an effort to provide therapeutically effective inhibitors of fungal dihydrofolate reductase (DHFR), we have cloned, expressed, purified, crystallized, and determined the three-dimensional structure of Candida albicans DHFR. The 192-residue enzyme, which was expressed in Escherichia coli and purified by methotrexate affinity and cation exchange chromatography, was 27% identical to human DHFR. Crystals of C. albicans DHFR were grown as the holoenzyme complex and as a ternary complex containing a pyrroloquinazoline inhibitor. Both complexes crystallized with two molecules in the asymmetric unit in space group P21. The final structures had R-factors of 0.199 at 1.85-A resolution and 0.155 at 1.60-A resolution, respectively. The enzyme fold was similar to that of bacterial and vertebrate DHFR, and the binding of a nonselective diaminopyrroloquinazoline inhibitor and the interactions of NADPH with protein were typical of ligand binding to other DHFRs. However, the width of the active site cleft of C. albicans DHFR was significantly larger than that of the human enzyme, providing a basis for the design of potentially selective inhibitors. | |||
X-ray crystallographic studies of Candida albicans dihydrofolate reductase. High resolution structures of the holoenzyme and an inhibited ternary complex.,Whitlow M, Howard AJ, Stewart D, Hardman KD, Kuyper LF, Baccanari DP, Fling ME, Tansik RL J Biol Chem. 1997 Nov 28;272(48):30289-98. PMID:9374515<ref>PMID:9374515</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1aoe" style="background-color:#fffaf0;"></div> | |||
== | |||
==See Also== | ==See Also== | ||
*[[Dihydrofolate reductase]] | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Candida albicans]] | [[Category: Candida albicans]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Howard | [[Category: Howard AJ]] | ||
[[Category: Stewart | [[Category: Stewart D]] | ||
[[Category: Whitlow | [[Category: Whitlow M]] | ||
Latest revision as of 13:54, 2 August 2023
CANDIDA ALBICANS DIHYDROFOLATE REDUCTASE COMPLEXED WITH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NADPH) AND 1,3-DIAMINO-7-(1-ETHYEPROPYE)-7H-PYRRALO-[3,2-F]QUINAZOLINE (GW345)CANDIDA ALBICANS DIHYDROFOLATE REDUCTASE COMPLEXED WITH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE (NADPH) AND 1,3-DIAMINO-7-(1-ETHYEPROPYE)-7H-PYRRALO-[3,2-F]QUINAZOLINE (GW345)
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 PubMedThe recent rise in systemic fungal infections has created a need for the development of new antifungal agents. As part of an effort to provide therapeutically effective inhibitors of fungal dihydrofolate reductase (DHFR), we have cloned, expressed, purified, crystallized, and determined the three-dimensional structure of Candida albicans DHFR. The 192-residue enzyme, which was expressed in Escherichia coli and purified by methotrexate affinity and cation exchange chromatography, was 27% identical to human DHFR. Crystals of C. albicans DHFR were grown as the holoenzyme complex and as a ternary complex containing a pyrroloquinazoline inhibitor. Both complexes crystallized with two molecules in the asymmetric unit in space group P21. The final structures had R-factors of 0.199 at 1.85-A resolution and 0.155 at 1.60-A resolution, respectively. The enzyme fold was similar to that of bacterial and vertebrate DHFR, and the binding of a nonselective diaminopyrroloquinazoline inhibitor and the interactions of NADPH with protein were typical of ligand binding to other DHFRs. However, the width of the active site cleft of C. albicans DHFR was significantly larger than that of the human enzyme, providing a basis for the design of potentially selective inhibitors. X-ray crystallographic studies of Candida albicans dihydrofolate reductase. High resolution structures of the holoenzyme and an inhibited ternary complex.,Whitlow M, Howard AJ, Stewart D, Hardman KD, Kuyper LF, Baccanari DP, Fling ME, Tansik RL J Biol Chem. 1997 Nov 28;272(48):30289-98. PMID:9374515[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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