Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases
Department of Biochemistry and Molecular Pharmacology
Aminoglycosides; *Anti-Bacterial Agents; Binding Sites; Crystallography; *Drug Resistance, Microbial; Enterococcus; Eukaryotic Cells; Kanamycin Kinase; Molecular Sequence Data; Phosphotransferases (Alcohol Group Acceptor); Protein Kinases; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Signal Transduction; Staphylococcus
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Bacterial resistance to aminoglycoside antibiotics is almost exclusively accomplished through either phosphorylation, adenylylation, or acetylation of the antibacterial agent. The aminoglycoside kinase, APH(3')-IIIa, catalyzes the phosphorylation of a broad spectrum of aminoglycoside antibiotics. The crystal structure of this enzyme complexed with ADP was determined at 2.2 A. resolution. The three-dimensional fold of APH(3')-IIIa reveals a striking similarity to eukaryotic protein kinases despite a virtually complete lack of sequence homology. Nearly 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 second-substrate specificity. These results indicate that APH(3') enzymes and eukaryotic-type protein kinases share a common ancestor.
DOI of Published Version
Cell. 1997 Jun 13;89(6):887-95. doi:10.1016/S0092-8674(00)80274-3
Hon WC, McKay GA, Thompson PR, Sweet RM, Yang DS, Wright GD, Berghuis AM. (1997). Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Thompson Lab Publications. https://doi.org/10.1016/S0092-8674(00)80274-3. Retrieved from https://escholarship.umassmed.edu/thompson/96