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==Candida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine (UCP120B)==
==Candida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine (UCP120B)==
<StructureSection load='3qlw' size='340' side='right' caption='[[3qlw]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
<StructureSection load='3qlw' size='340' side='right'caption='[[3qlw]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3qlw]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_11006_[[candida_stellatoidea]] Atcc 11006 [[candida stellatoidea]]]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QLW FirstGlance]. <br>
<table><tr><td colspan='2'>[[3qlw]] 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=3QLW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QLW FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N22:5-[3-(2,5-DIMETHOXYPHENYL)PROP-1-YN-1-YL]-6-ETHYLPYRIMIDINE-2,4-DIAMINE'>N22</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.504&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1m78|1m78]], [[1m79|1m79]], [[1m7a|1m7a]], [[1ia1|1ia1]], [[1ia2|1ia2]], [[1ia3|1ia3]], [[1ia4|1ia4]], [[1aoe|1aoe]], [[1ai9|1ai9]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N22:5-[3-(2,5-DIMETHOXYPHENYL)PROP-1-YN-1-YL]-6-ETHYLPYRIMIDINE-2,4-DIAMINE'>N22</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CaJ7.0360, CaO19.12607, CaO19.5142, DFR1, DHFR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5476 ATCC 11006 [[Candida stellatoidea]]])</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=3qlw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlw OCA], [https://pdbe.org/3qlw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qlw RCSB], [https://www.ebi.ac.uk/pdbsum/3qlw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qlw ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlw RCSB], [http://www.ebi.ac.uk/pdbsum/3qlw PDBsum]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[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.
Candida albicans and Candida glabrata cause fungal bloodstream infections that are associated with significant mortality. As part of an effort to develop potent and selective antifolates that target dihydrofolate reductase (DHFR) from Candida species, we report three ternary crystal structures of Candida albicans DHFR (CaDHFR) bound to novel propargyl-linked analogs. Consistent with earlier modeling results, these structures show that hydrophobic pockets in the binding site may be exploited to increase ligand potency. The crystal structures also confirm that loop residues Thr 58- Phe 66, which flank the active site and influence ligand potency and selectivity, adopt multiple conformations. To aid the development of a dual Candida spp. inhibitor, three new crystal structures of C. glabrata DHFR (CgDHFR) bound to similar ligands as those bound in the ternary structures of CaDHFR are also reported here. Loop residues 58-66 in CgDHFR and human DHFR are 1 A and 3 A closer to the folate binding site, respectively, than loop residues in CaDHFR, suggesting that a properly size ligand could be a potent and selective dual inhibitor of CaDHFR and CgDHFR.
 
Crystal structures of Candida albicans dihydrofolate reductase bound to propargyl-linked antifolates reveal the flexibility of active site loop residues critical for ligand potency and selectivity.,Paulsen JL, Bendel SD, Anderson AC Chem Biol Drug Des. 2011 Jul 5. doi: 10.1111/j.1747-0285.2011.01169.x. PMID:21726415<ref>PMID:21726415</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Anderson, A C]]
[[Category: Candida albicans]]
[[Category: Bendel, S D]]
[[Category: Large Structures]]
[[Category: Paulsen, J L]]
[[Category: Anderson AC]]
[[Category: Antifungal agent]]
[[Category: Bendel SD]]
[[Category: Candida albican]]
[[Category: Paulsen JL]]
[[Category: Drug design]]
[[Category: Enzyme inhibitor]]
[[Category: Fungal protein]]
[[Category: Model]]
[[Category: Molecular structure]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
[[Category: Structure-activity relationship]]
[[Category: Tetrahydrofolate dehydrogenase]]

Latest revision as of 14:50, 14 March 2024

Candida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine (UCP120B)Candida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine (UCP120B)

Structural highlights

3qlw is a 2 chain structure with sequence from Candida albicans. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.504Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DYR_CANAX Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.

3qlw, resolution 2.50Å

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