Primary Citation of Related Structures: 8EV6, 8EV7, 8SYL
PubMed Abstract:
Aminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of kanamycin, is commonly used for treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria. Amikacin carries the 4-amino-2-hydroxy butyrate (AHB) moiety at the N 1 amino group of the central 2-deoxystreptamine (2-DOS) ring, which may confer amikacin a unique ribosome inhibition profile. Here we use in vitro fast kinetics combined with X-ray crystallography and cryo-EM to dissect the mechanisms of ribosome inhibition by amikacin and the parent compound, kanamycin. Amikacin interferes with tRNA translocation, release factor-mediated peptidyl-tRNA hydrolysis, and ribosome recycling, traits attributed to the additional interactions amikacin makes with the decoding center. The binding site in the large ribosomal subunit proximal to the 3'-end of tRNA in the peptidyl (P) site lays the groundwork for rational design of amikacin derivatives with improved antibacterial properties.
Organizational Affiliation:
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden.
Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden. suparna.sanyal@icm.uu.se.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA. magagnon@utmb.edu.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA. magagnon@utmb.edu.
Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, 77555, USA. magagnon@utmb.edu.
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, 77555, USA. magagnon@utmb.edu.
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