Details

Autor(en) / Beteiligte

• Bulkley, David
• Brandi, Letizia
• Polikanov, Yury S.
• Fabbretti, Attilio
• O’Connor, Michael
• Gualerzi, Claudio O.
• Steitz, Thomas A.

Titel

The Antibiotics Dityromycin and GE82832 Bind Protein S12 and Block EF-G-Catalyzed Translocation

Ist Teil von

• Cell reports (Cambridge), 2014-01, Vol.6 (2), p.357-365

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The translocation of mRNA and tRNA through the ribosome is catalyzed by elongation factor G (EF-G), a universally conserved guanosine triphosphate hydrolase (GTPase). The mechanism by which the closely related decapeptide antibiotics dityromycin and GE82832 inhibit EF-G-catalyzed translocation is elucidated in this study. Using crystallographic and biochemical experiments, we demonstrate that these antibiotics bind to ribosomal protein S12 in solution alone as well as within the small ribosomal subunit, inducing long-range effects on the ribosomal head. The crystal structure of the antibiotic in complex with the 70S ribosome reveals that the binding involves conserved amino acid residues of S12 whose mutations result in in vitro and in vivo antibiotic resistance and loss of antibiotic binding. The data also suggest that GE82832/dityromycin inhibits EF-G-catalyzed translocation by disrupting a critical contact between EF-G and S12 that is required to stabilize the posttranslocational conformation of EF-G, thereby preventing the ribosome-EF-G complex from entering a conformation productive for translocation. [Display omitted] •GE82832 and dityromycin bind to protein S12 alone and within the 30S subunit•GE82832/dityromycin binding causes long-range conformational changes of the 30S head•GE82832/dityromycin blocks 70S-bound EF-G from entering the posttranslocation state Gualerzi, Steitz, and colleagues report the structural and biochemical characterization of the antibiotics GE82832 and dityromycin. GE82832/dityromycin interacts with a region of protein S12 (on the small ribosomal subunit) that has not been identified as a target for antibiotics but plays a critical role in translation. These findings suggest that these antibiotics inhibit translocation by blocking a contact between EF-G and the ribosome that is required for the formation of the posttranslocation complex.