The antibiotics dityromycin and GE82832 bind protein S12 and block EF-G-catalyzed translocation.

Publication Type:

Journal Article


Cell Rep, Volume 6, Issue 2, p.357-65 (2014)


Amino Acid Sequence, Anti-Bacterial Agents, Bacterial Proteins, Binding Sites, Escherichia coli, Molecular Docking Simulation, Molecular Sequence Data, Peptide Chain Elongation, Translational, Peptide Elongation Factor 2, Peptides, Protein Binding, Thermus thermophilus


<p>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.</p>

4V9R 4V9S