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Structures cristallographiques de complexes entre des fragments d'acides ribonucléiques comportant le site A ribosomique et des antibiotiques de la famille des aminoglycosides

Abstract : Aminoglycoside antibiotics are aminosugar derivatives that interfere with protein translation in bacteria by binding to the aminoacyl-transfer RNA decoding site (A site) located at the 3' end of the 16S ribosomal RNA. This work presents the X-ray crystal structures of three complexes formed between RNA fragments contraining the A site and the aminoglycosides paromomycin, tobramycin and geneticin, solved at 2,40-2,54 Å resolutions. The structural analysis shows that the specific molecular recognition and the binding of aminoglycosides to the A site involve several direct and water-mediated hydrogen bonds. In the different structures, the neamine moiety common to the aminoglycosides (rings I and II) intercalates similarly inside the helix: ring I makes a pseudo base pair with adenine 1408, and both rings I and II flip out adenines 1492 and 1493. The comparison of the 3D structures of those complexes enables to rationalize the various biochemical and microbiological results as well as some of resistance and toxicity mechanisms at the molecular level. The conformations of the A site and the aminoglycosides are similar to those observed for the A site bound to paromomycin in the crystal structure of the 30S ribosomal particle. Hence, the method presented here provides a more precise description of the interactions and of the mode of action of aminoglycosides that is essential to deepen our knowledge of the RNA/aminoglycoside system. These results should facilitate the design of more specific and less toxic antibiotics.
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Contributor : Quentin Vicens <>
Submitted on : Friday, October 17, 2003 - 5:07:06 AM
Last modification on : Thursday, April 23, 2020 - 2:26:32 PM
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Quentin Vicens. Structures cristallographiques de complexes entre des fragments d'acides ribonucléiques comportant le site A ribosomique et des antibiotiques de la famille des aminoglycosides. Médicaments. Université Louis Pasteur - Strasbourg I, 2002. Français. ⟨tel-00003572⟩

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