Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
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.
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Citation: Cell. 1997 Jun 13;89(6):887-95. doi:10.1016/S0092-8674(00)80274-3
Hon, W. C.; McKay, G. A.; Thompson, Paul R.; Sweet, R. M.; Yang, D. S.; Wright, G. D.; and Berghuis, A. M., "Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases" (1997). Thompson Lab Publications. 96.