CRYSTAL-STRUCTURE OF THE ANTIFUNGAL TARGET N-MYRISTOYL TRANSFERASE

N-myristoyl transferase (NMT) catalyzes the transfer of the fatty acid myristate from myristoyl-CoA to the N-terminal glycine of substrate p roteins, and is found only in eukaryotic cells. The enzyme in this stu dy is the 451 amino acid protein produced by Candida albicans, a yeast responsible for the majority of systemic infections in immune-comprom ised humans. NMT activity is essential for vegetative growth, and the structure was determined in order to assist in the discovery of a sele ctive inhibitor of NMT which could be developed as an anti-fungal drug , NMT has no sequence homology with other protein sequences and has a never alpha/beta fold which shows internal twofold symmetry, which may be a result of gene duplication. On one face of the protein there is a long. curved, relatively uncharged groove, at the center of which is a deep pocket. The pocket floor is negatively charged due to the vici nity of the C-terminal carboxylate and a nearby conserved glutamic: ac id residue, which separates the pocket from a cavity. These observatio ns, considered alongside the positions of residues whose mutation affe cts substrate binding and activity, suggest that the groove and pocket are the sites of substrate binding and the floor of the pocket is the catalytic center.