Crystal structures of Candida albicans N-myristoyltransferase with two distinct inhibitors.

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Sogabe S, Masubuchi M, Sakata K, Fukami TA, Morikami K, Shiratori Y, Ebiike H, Kawasaki K, Aoki Y, Shimma N, D'Arcy A, Winkler FK, Banner DW, Ohtsuka T

Crystal structures of Candida albicans N-myristoyltransferase with two distinct inhibitors.

Chem Biol. 2002 Oct;9(10):1119-28.

PubMed ID

12401496 [ View in PubMed

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Abstract

Myristoyl-CoA:protein N-myristoyltransferase (Nmt) is a monomeric enzyme that catalyzes the transfer of the fatty acid myristate from myristoyl-CoA to the N-terminal glycine residue of a variety of eukaryotic and viral proteins. Genetic and biochemical studies have established that Nmt is an attractive target for antifungal drugs. We present here crystal structures of C. albicans Nmt complexed with two classes of inhibitor competitive for peptide substrates. One is a peptidic inhibitor designed from the peptide substrate; the other is a nonpeptidic inhibitor having a benzofuran core. Both inhibitors are bound into the same binding groove, generated by some structural rearrangements of the enzyme, with the peptidic inhibitor showing a substrate-like binding mode and the nonpeptidic inhibitor binding differently. Further, site-directed mutagenesis for C. albicans Nmt has been utilized in order to define explicitly which amino acids are critical for inhibitor binding. The results suggest that the enzyme has some degree of flexibility for substrate binding and provide valuable information for inhibitor design.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Glycylpeptide N-tetradecanoyltransferase	P30418	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(1-Methyl-1h-Imidazol-2-Yl)-(3-Methyl-4-{3-[(Pyridin-3-Ylmethyl)-Amino]-Propoxy}-Benzofuran-2-Yl)-Methanone	Glycylpeptide N-tetradecanoyltransferase 1	IC 50 (nM)	69	N/A	N/A	Details