Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 44, Pages 22275-22281Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1909831116
Keywords
ribosome; antibiotic; resistance; aminoglycoside; cystic fibrosis
Categories
Funding
- European Research Council [322581]
- Kimmelman Center for Macromolecular Assemblies
- Danish Council for Independent Research [DFF-4181-00115]
- Novo Nordisk Foundation
- iNEXT: Infrastructure for NMR, EM and X-Rays for Translational Research Project - European Union Horizon 2020 program [653706]
- Technical University of Denmark
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Resistance to antibiotics has become a major threat to modern medicine. The ribosome plays a fundamental role in cell vitality by the translation of the genetic code into proteins; hence, it is a major target for clinically useful antibiotics. We report here the cryo-electron microscopy structures of the ribosome of a pathogenic aminoglycoside (AG)-resistant Pseudomonas aeruginosa strain, as well as of a nonresistance strain isolated from a cystic fibrosis patient. The structural studies disclosed defective ribosome complex formation due to a conformational change of rRNA helix H69, an essential intersubunit bridge, and a secondary binding site of the AGs. In addition, a stable conformation of nucleotides A1486 and A1487, pointing into helix h44, is created compared to a non-AG-bound ribosome. We suggest that altering the conformations of ribosomal protein uL6 and rRNA helix H69, which interact with initiation-factor IF2, interferes with proper protein synthesis initiation.
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