STRUCTURE OF AN ENZYME REQUIRED FOR AMINOGLYCOSIDE ANTIBIOTIC-RESISTANCE REVEALS HOMOLOGY TO EUKARYOTIC PROTEIN-KINASES

Bacterial resistance to aminoglycoside antibiotics is almost exclusive ly accomplished through either phosphorylation, adenylylation, or acet ylation of the antibacterial agent. The aminoglycoside kinase, APH(3') IIIa, catalyzes the phosphorylation of a broad spectrum of aminoglycos ide antibiotics. The crystal structure of this enzyme complexed with A DP was determined at 2.2 Angstrom resolution. The three-dimensional fo ld of APH(3')-IIIa reveals a striking similarity to eukaryotic protein kinases despite a virtually complete lack of sequence homology. Nearl y half of the APH(3')-IIIa sequence adopts a conformation identical to that seen in these kinases. Substantial differences are found in the location and conformation of residues presumably responsible for secon d-substrate specificity. These results indicate that APH(3') enzymes a nd eukaryotic-type protein kinases share a common ancestor.