4CAX: Crystal Structure Of Aspergillus Fumigatus N-myristoyl Transferase In Complex With Myristoyl Coa And A Pyrazole Sulphonamide Ligand (ddd85646)

Citation:
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.
PDB ID: 4CAXDownload
MMDB ID: 123168
PDB Deposition Date: 2013/10/9
Updated in MMDB: 2014/09
Experimental Method:
x-ray diffraction
Resolution: 1.85  Å
Source Organism:
Similar Structures:
Biological Unit for 4CAX: monomeric; determined by author and by software (PISA)
Molecular Components in 4CAX
Label Count Molecule
Protein (1 molecule)
1
Glycylpeptide N-tetradecanoyltransferase(Gene symbol: AFUA_4G08070)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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