title: Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases.
abstract: 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.
authors.affiliation: Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
authors.forename: W C
authors.initials: WC
authors.lastname: Hon
authors.forename: G A
authors.initials: GA
authors.lastname: McKay
authors.forename: P R
authors.initials: PR
authors.lastname: Thompson
authors.forename: R M
authors.initials: RM
authors.lastname: Sweet
authors.forename: D S
authors.initials: DS
authors.lastname: Yang
authors.forename: G D
authors.initials: GD
authors.lastname: Wright
authors.forename: A M
authors.initials: AM
authors.lastname: Berghuis
mesh_terms: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001665:Binding Sites / Q000502:physiology; D003461:Crystallography; D004352:Drug Resistance, Microbial; D016983:Enterococcus / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D005057:Eukaryotic Cells / Q000201:enzymology*; D019868:Kanamycin Kinase; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D013210:Staphylococcus / Q000737:chemistry / Q000201:enzymology / Q000235:genetics
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019868:Kanamycin Kinase