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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)== | |||
<StructureSection load='3qlw' size='340' side='right' caption='[[3qlw]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== 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> | |||
</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> | |||
<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='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'>[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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
[[Category: Anderson, A C | == References == | ||
[[Category: Bendel, S D | <references/> | ||
[[Category: Paulsen, J L | __TOC__ | ||
</StructureSection> | |||
[[Category: Anderson, A C]] | |||
[[Category: Bendel, S D]] | |||
[[Category: Paulsen, J L]] | |||
[[Category: Antifungal agent]] | [[Category: Antifungal agent]] | ||
[[Category: Candida albican]] | [[Category: Candida albican]] | ||
Revision as of 09:45, 21 December 2014
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
Publication Abstract from PubMedCandida 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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