Molecular recognition between the ribosomal decoding site and natural or non-natural aminoglycosides

Abstract

Crystal structures of complexes between ribosomal particles and antibiotics have pinned down very precisely the discrete binding sites of several classes of antibiotics inhibiting protein synthesis. The crystal structures of complexes between various antibiotics and ribosomal particles show definitively that ribosomal RNAs, rather than ribosomal proteins, are overwhelmingly targeted. The comparative analysis of various aminoglycosides bound to the same site has been used to decipher the contribution of each functional group to the RNA/aminoglycoside complex and to attempt to rationalize various biochemical and microbiological data as well as some resistance and toxicity mechanisms at the molecular level. Tight packing of atoms in direct van der Waals contact is central and a prerequisite to specific recognition. Water molecules participate in the assembly by linking hydrophilic groups belonging to both components. The hydration shells around nucleic acid base pairs tend to be conserved and maintained whatever the environment. Two regions are crucial for specificity and resistance: A1408 and the non-Watson-Crick pair U1406-U1495.