Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases.
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.
Hon
W C
WC
Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
McKay
G A
GA
Thompson
P R
PR
Sweet
R M
RM
Yang
D S
DS
Wright
G D
GD
Berghuis
A M
AM
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
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019868:Kanamycin Kinase