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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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Structural Basis for the Binding of RX-01, a Novel Oxazolidinone Class, to Bacterial Ribosomesтезисы доклада
- Авторы: IPPOLITO J., KANYO Z., WIMBERLY B., WANG D., SKRIPKIN E., DEVITO J., FREEBORN B., SUTCLIFFE J., DUFFY E., FRANCESCHI F.
- Сборник: 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), December 16 – 19, 2005
- Тезисы
- Год издания: 2005
- Место издания: ASM, Washington, DC, USA
- Первая страница: F-1254
- Аннотация: Background: The RX-01 class of designer oxazolidinones targets the large ribosomal subunit (50S). Oxazolidinones have been proposed to inhibit translation by interfering with the binding of initiator f-Met-tRNA and to promote translational inaccuracy. To gain structural insights into their mechanism of action, the X-ray structures of multiple compounds from this class as well as the exemplar oxazolidinone, linezolid, bound to the 50S ribosomal subunit of Haloarcula marismortui were determined. Methods: Using X-ray crystallographic methods, complexes of several oxazolidinones bound to H. marismortui 50S were solved. Corroborating evidence was gained through RNA footprinting using ribosomes isolated from several bacterial sources. Additionally, several compounds from the RX-01 class were assessed for their ability to induce translational frameshifting using b- galactosidase protein fusions containing missense or nonsense mutations. Results: The 50S-oxazolidinone structures revealed that oxazolidinones bind in the 50S A-site, near the peptidyl transferase center. The oxazolidinone ring and the pendant acetamide pack tightly against the terminus of the A-site cavity while the phenyl ring takes advantage of aromatic stacking interactions in a perfectly-formed hydrophobic crevice. RNA footprinting experiments of complexes of RX-01 compounds with bacterial 70S or 50S ribosomes provided independent evidence that in solution the RX-01 class bound in the A-site. Taken together, these results contrast with previous biochemical studies positioning oxazolidinones in the 50S P-site. Moreover, the RX-01 class, like other oxazolidinones, is able to promote translational frameshifting. Conclusion: Crystallographic and footprinting experiments showed that oxazolidinones bound in the 50S ribosomal A-site and promoted translational inaccuracy.
- Добавил в систему: Скрипкин Евгений Алексеевич