4A5O

Crystal structure of Pseudomonas aeruginosa N5, N10- methylenetetrahydrofolate dehydrogenase-cyclohydrolase (FolD)

Summary for 4A5O

• Entry DOI: 10.2210/pdb4a5o/pdb
• Descriptor: BIFUNCTIONAL PROTEIN FOLD, GLYCEROL, DI(HYDROXYETHYL)ETHER, ... (4 entities in total)
• Functional Keywords: oxidoreductase, hydrolase
• Biological source: PSEUDOMONAS AERUGINOSA PAO1
• Total number of polymer chains: 4
• Total formula weight: 123319.56

Authors

Eadsforth, T.C.,Gardiner, M.,Maluf, F.V.,McElroy, S.,James, D.,Frearson, J.,Gray, D.,Hunter, W.N. (deposition date: 2011-10-26, release date: 2011-11-16, Last modification date: 2023-12-20)

Primary citation

Eadsforth, T.C.,Gardiner, M.,Maluf, F.V.,Mcelroy, S.,James, D.,Frearson, J.,Gray, D.,Hunter, W.N.
Assessment of Pseudomonas Aeruginosa N(5),N(10)-Methylenetetrahydrofolate Dehydrogenase - Cyclohydrolase as a Potential Antibacterial Drug Target.
Plos One, 7:35973-, 2012

PubMed Abstract: The 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 Å 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.

PubMed: 22558288
DOI: 10.1371/JOURNAL.PONE.0035973

Experimental method

X-RAY DIFFRACTION (2.2 Å)