4CAX

Crystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a pyrazole sulphonamide ligand (DDD85646)

Summary for 4CAX

• Entry DOI: 10.2210/pdb4cax/pdb
• Related: 4CAV 4CAW
• Descriptor: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, TETRADECANOYL-COA, 2,6-dichloro-4-(2-piperazin-1-ylpyridin-4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzenesulfonamide, ... (4 entities in total)
• Functional Keywords: transferase, drug discovery
• Biological source: ASPERGILLUS FUMIGATUS
• Cellular location: Cytoplasm: Q9UVX3
• Total number of polymer chains: 1
• Total formula weight: 48916.57

Authors

Raimi, O.G.,Robinson, D.A.,Fang, W.,Blair, D.E.,Harrison, J.,Ruda, G.F.,Lockhart, D.E.A.,Torrie, L.S.,Wyatt, P.G.,Gilbert, I.H.,Van Aalten, D.M.F. (deposition date: 2013-10-09, release date: 2014-09-17, Last modification date: 2024-05-08)

Primary citation

Fang, W.,Robinson, D.A.,Raimi, O.G.,Blair, D.E.,Harrison, J.R.,Lockhart, D.E.A.,Torrie, L.S.,Ruda, G.F.,Wyatt, P.G.,Gilbert, I.H.,Van Aalten, D.M.F.
N-Myristoyltransferase is a Cell Wall Target in Aspergillus Fumigatus.
Acs Chem.Biol., 10:1425-, 2015

PubMed Abstract: Treatment of filamentous fungal infections relies on a limited repertoire of antifungal agents. Compounds possessing novel modes of action are urgently required. N-myristoylation is a ubiquitous modification of eukaryotic proteins. The enzyme N-myristoyltransferase (NMT) has been considered a potential therapeutic target in protozoa and yeasts. Here, we show that the filamentous fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is essential for survival. Surprisingly, partial repression of the gene revealed downstream effects of N-myristoylation on cell wall morphology. Screening a library of inhibitors led to the discovery of a pyrazole sulphonamide compound that inhibits the enzyme and is fungicidal under partially repressive nmt conditions. Together with a crystallographic complex showing the inhibitor binding in the peptide substrate pocket, we provide evidence of NMT being a potential drug target in A. fumigatus.

PubMed: 25706802
DOI: 10.1021/CB5008647

Experimental method

X-RAY DIFFRACTION (1.85 Å)