4a5o: Difference between revisions
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==Crystal structure of Pseudomonas aeruginosa N5, N10- methylenetetrahydrofolate dehydrogenase-cyclohydrolase (FolD)== | ==Crystal structure of Pseudomonas aeruginosa N5, N10- methylenetetrahydrofolate dehydrogenase-cyclohydrolase (FolD)== | ||
<StructureSection load='4a5o' size='340' side='right' caption='[[4a5o]], [[Resolution|resolution]] 2.20Å' scene=''> | <StructureSection load='4a5o' size='340' side='right'caption='[[4a5o]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4a5o]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4a5o]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A5O FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.2Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=4a5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a5o OCA], [https://pdbe.org/4a5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a5o RCSB], [https://www.ebi.ac.uk/pdbsum/4a5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a5o ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/FOLD_PSEAE FOLD_PSEAE] Catalyzes the oxidation of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate and then the hydrolysis of 5,10-methenyltetrahydrofolate to 10-formyltetrahydrofolate.<ref>PMID:22558288</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 22: | Line 23: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Eadsforth | [[Category: Pseudomonas aeruginosa PAO1]] | ||
[[Category: Frearson | [[Category: Eadsforth TC]] | ||
[[Category: Gardiner | [[Category: Frearson J]] | ||
[[Category: Gray | [[Category: Gardiner M]] | ||
[[Category: Hunter | [[Category: Gray D]] | ||
[[Category: James | [[Category: Hunter WN]] | ||
[[Category: Maluf | [[Category: James D]] | ||
[[Category: | [[Category: Maluf FV]] | ||
[[Category: McElroy S]] | |||
Latest revision as of 14:19, 20 December 2023
Crystal structure of Pseudomonas aeruginosa N5, N10- methylenetetrahydrofolate dehydrogenase-cyclohydrolase (FolD)Crystal structure of Pseudomonas aeruginosa N5, N10- methylenetetrahydrofolate dehydrogenase-cyclohydrolase (FolD)
Structural highlights
FunctionFOLD_PSEAE Catalyzes the oxidation of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate and then the hydrolysis of 5,10-methenyltetrahydrofolate to 10-formyltetrahydrofolate.[1] Publication Abstract from PubMedThe bifunctional enzyme methylenetetrahydrofolate dehydrogenase - cyclohydrolase (FolD) is identified as a potential drug target in Gram-negative bacteria, in particular the troublesome Pseudomonas aeruginosa. In order to provide a comprehensive and realistic assessment of the potential of this target for drug discovery we generated a highly efficient recombinant protein production system and purification protocol, characterized the enzyme, carried out screening of two commercial compound libraries by differential scanning fluorimetry, developed a high-throughput enzyme assay and prosecuted a screening campaign against almost 80,000 compounds. The crystal structure of P. aeruginosa FolD was determined at 2.2 A resolution and provided a template for an assessment of druggability and for modelling of ligand complexes as well as for comparisons with the human enzyme. New FolD inhibitors were identified and characterized but the weak levels of enzyme inhibition suggest that these compounds are not optimal starting points for future development. Furthermore, the close similarity of the bacterial and human enzyme structures suggest that selective inhibition might be difficult to attain. In conclusion, although the preliminary biological data indicates that FolD represents a valuable target for the development of new antibacterial drugs, indeed spurred us to investigate it, our screening results and structural data suggest that this would be a difficult enzyme to target with respect to developing the appropriate lead molecules required to underpin a serious drug discovery effort. Assessment of Pseudomonas aeruginosa N(5),N(10)-Methylenetetrahydrofolate Dehydrogenase - Cyclohydrolase as a Potential Antibacterial Drug Target.,Eadsforth TC, Gardiner M, Maluf FV, McElroy S, James D, Frearson J, Gray D, Hunter WN PLoS One. 2012;7(4):e35973. Epub 2012 Apr 25. PMID:22558288[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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