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NMR structures of promising antibiotic for characterization of the ribosomal binding site

3 May 2011. Thiopeptides such as thiostrepton are highly modified macrocyclic natural products that originate from ribosomal peptide biosynthesis. Despite their exceptional activity in vitro, thiopeptides are not used in human medical therapy, mainly because of their very low solubility. Thiostrepton prominently inhibits protein biosynthesis by binding to the GTPase-associated region (GAR) on the ribosome. The identification of derivatives with improved pharmakinetics has been hampered by a lack of information on the key interactions with the adaptive ribosomal RNA and proteins. A team of scientists from Frankfurt and Dortmund have now determined the activity of thiostrepton and derivatives with targeted shape changes at their ribosomal binding site using semisynthesis, NMR structure determination, docking, and biological evaluation in an integrated fashion. This combination revealed important elements of molecular recognition within the embedded pharmocophore of the target, a composite RNA–protein complex.

Link to publication in the journal Angewandte Chemie

 

Contact
Harald Schwalbe
Goethe University
Institute for Organic Chemistry and Chemical Biology
Max-von-Laue-Strasse 7
60438 Frankfurt am Main, Germany 

 

Full reference
Jonker, H. R. A., Baumann, S., Wolf, A., Schoof, S., Hiller, F., Schulte, K. W., Kirschner, K. N., Schwalbe, H. and Arndt, H.-D. (2011), NMR Structures of Thiostrepton Derivatives for Characterization of the Ribosomal Binding Site. Angewandte Chemie International Edition, 50: 3308–3312. doi: 10.1002/anie.201003582