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Antibiotics 2016, 5(4), 38; doi:10.3390/antibiotics5040038

Conformational Response of 30S-bound IF3 to A-Site Binders Streptomycin and Kanamycin

1
Centro de Investigación e Innovación, Faculty of Health Sciences, Universidad Peruana de Ciencias Aplicadas—UPC, Lima L-33, Peru
2
Facultad de Ciencias y Filosofía Alberto Cazorla Talleri, Universidad Peruana Cayetano Heredia—UPCH, Lima L-31, Peru
3
Laboratory of Genetics, Department of Biosciences and Veterinary Medicine, University of Camerino, 62032 Camerino, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Claudio O. Gualerzi
Received: 20 April 2016 / Revised: 22 October 2016 / Accepted: 6 December 2016 / Published: 13 December 2016
(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)
View Full-Text   |   Download PDF [8185 KB, uploaded 14 December 2016]   |  

Abstract

Aminoglycoside antibiotics are widely used to treat infectious diseases. Among them, streptomycin and kanamycin (and derivatives) are of importance to battle multidrug-resistant (MDR) Mycobacterium tuberculosis. Both drugs bind the small ribosomal subunit (30S) and inhibit protein synthesis. Genetic, structural, and biochemical studies indicate that local and long-range conformational rearrangements of the 30S subunit account for this inhibition. Here, we use intramolecular FRET between the C- and N-terminus domains of the flexible IF3 to monitor real-time perturbations of their binding sites on the 30S platform. Steady and pre-steady state binding experiments show that both aminoglycosides bring IF3 domains apart, promoting an elongated state of the factor. Binding of Initiation Factor IF1 triggers closure of IF3 bound to the 30S complex, while both aminoglycosides revert the IF1-dependent conformation. Our results uncover dynamic perturbations across the 30S subunit, from the A-site to the platform, and suggest that both aminoglycosides could interfere with prokaryotic translation initiation by modulating the interaction between IF3 domains with the 30S platform. View Full-Text
Keywords: streptomycin; kanamycin; translation initiation; 30S subunit; IF3; tuberculosis; FRET streptomycin; kanamycin; translation initiation; 30S subunit; IF3; tuberculosis; FRET
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MDPI and ACS Style

Chulluncuy, R.; Espiche, C.; Nakamoto, J.A.; Fabbretti, A.; Milón, P. Conformational Response of 30S-bound IF3 to A-Site Binders Streptomycin and Kanamycin. Antibiotics 2016, 5, 38.

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