View source for 4hoe


==Candida albicans dihydrofolate reductase complexed with NADPH and 5-[3-(2,5-dimethoxy-4-phenylphenyl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine (UCP111E)==
<StructureSection load='4hoe' size='340' side='right'caption='[[4hoe]], [[Resolution|resolution]] 1.76&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4hoe]] 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=4HOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HOE 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]] 1.76&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=18G:5-[3-(2,5-DIMETHOXY-4-PHENYLPHENYL)BUT-1-YN-1-YL]-6-METHYLPYRIMIDINE-2,4-DIAMINE'>18G</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4hoe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hoe OCA], [https://pdbe.org/4hoe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hoe RCSB], [https://www.ebi.ac.uk/pdbsum/4hoe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hoe 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 mug/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.

Propargyl-Linked Antifolates are Dual Inhibitors of Candida albicans and Candida glabrata.,G-Dayanandan N, Paulsen JL, Viswanathan K, Keshipeddy S, Lombardo MN, Zhou W, Lamb KM, Sochia AE, Alverson JB, Priestley ND, Wright DL, Anderson AC J Med Chem. 2014 Mar 6. PMID:24568657<ref>PMID:24568657</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4hoe" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Candida albicans]]
[[Category: Large Structures]]
[[Category: Anderson AC]]
[[Category: Paulsen JL]]