title: Systematic approach to understanding macrolide-ribosome interactions: NMR and modeling studies of oleandomycin and its derivatives.
abstract: The three-dimensional structures of oleandomycin (1) and its derivatives oleandomycin-9-oxime (2) and 10,11-anhydrooleandomycin (3) were determined in different solvents by the combined use of NMR and molecular modeling methods. The experimental NMR data were compared with the results of molecular modeling and known crystal structures of the related molecules. It was shown that the dominant conformation of the lactone ring is the folded-out conformation with some amounts of the folded-in one depending on the solvent and temperature, while desosamine and cladinose sugars adopt the usual chair conformations. Modeling calculations provided evidence for conformational changes in the upper lactone region as well. Saturation transfer difference (STD) NMR experiments have provided information on the binding epitopes of 1-3 in complexes with E. coli ribosomes. The obtained molecular surfaces in close contact with ribosomes were compared with recently available 3D structures of the related macrolide-ribosome complexes, and the observed differences were discussed. The knowledge gained from this study can serve as a platform for the design of novel macrolides with an improved biological profile.
authors.affiliation: Faculty of Natural Sciences, Department of Analytical Chemistry, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia. pnovak@chem.pmf.hr
authors.forename: Predrag
authors.initials: P
authors.lastname: Novak
authors.forename: Iva
authors.initials: I
authors.lastname: Tatić
authors.forename: Predrag
authors.initials: P
authors.lastname: Tepes
authors.forename: Sanja
authors.initials: S
authors.lastname: Kostrun
authors.forename: Jill
authors.initials: J
authors.lastname: Barber
mesh_terms: D000900:Anti-Bacterial Agents; D001665:Binding Sites; D018942:Macrolides / Q000737:chemistry / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D009827:Oleandomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D012270:Ribosomes / Q000378:metabolism*; D012997:Solvents
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D012997:Solvents; D009827:Oleandomycin