Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 30, Pages 12283-12288Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1304922110
Keywords
peptidyl transfer; ribosome crystal structure; termination inhibitor; translation inhibitor; translation termination
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Funding
- US National Institute of Health [GM-099719, P30 GM092424]
- Worcester Foundation for Biomedical Research
- University of Massachusetts Medical School Center for AIDS Research
- X25 (National Synchrotron Light Source at Brookhaven National Laboratory, US Department of Energy) [DE-AC02-98CH10886]
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The antibiotic blasticidin S (BlaS) is a potent inhibitor of protein synthesis in bacteria and eukaryotes. We have determined a 3.4-angstrom crystal structure of BlaS bound to a 70S-tRNA ribosome complex and performed biochemical and single-molecule FRET experiments to determine the mechanism of action of the antibiotic. We find that BlaS enhances tRNA binding to the P site of the large ribosomal subunit and slows down spontaneous intersubunit rotation in pretranslocation ribosomes. However, the antibiotic has negligible effect on elongation factor G catalyzed translocation of tRNA and mRNA. The crystal structure of the antibiotic-ribosome complex reveals that BlaS impedes protein synthesis through a unique mechanism by bending the 3' terminus of the P-site tRNA toward the A site of the large ribosomal subunit. Biochemical experiments demonstrate that stabilization of the deformed conformation of the P-site tRNA by BlaS strongly inhibits peptidyl-tRNA hydrolysis by release factors and, to a lesser extent, peptide bond formation.
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