Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate

Yehuda Halfon; Alicia Jimenez-Fernandez; Ruggero La Rosa; Rocio Espinosa Portero; Helle Krogh Johansen; Donna Matzov; Zohar Eyal; Anat Bashan; Ella Zimmerman; Matthew Belousoff; Soren Molin; Ada Yonath

doi:10.1073/pnas.1909831116

Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate

Yehuda Halfon, Alicia Jimenez-Fernandez, Ruggero La Rosa, Rocio Espinosa Portero, Helle Krogh Johansen, Donna Matzov, Zohar Eyal, Anat Bashan, Ella Zimmerman, Matthew Belousoff, Soren Molin, Ada Yonath

Department of Chemical and Structural Biology

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	22275-22281
Number of pages	7
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	44
DOIs	https://doi.org/10.1073/pnas.1909831116
Publication status	Published - 29 Oct 2019

Funding

We thank the A.Y. and S.M. groups for their interest and experimental support; and Christoph Diebolde for EM data acquisition at NeCEN and helpful advice. This work was supported by European Research Council Grant 322581 (Novel Insights into Multi-Drug Resistance to Antibiotics and the Primordial Ribosome); the Kimmelman Center for Macromolecular Assemblies; Danish Council for Independent Research Grant Rammebevilling DFF-4181-00115; and the Novo Nordisk Foundation. This work was also supported by iNEXT: Infrastructure for NMR, EM and X-Rays for Translational Research Project 653706, funded by the European Union Horizon 2020 program. A.Y. holds the Martin S. and Helen Kimmel Professorial Chair at the Weizmann Institute of Science. A.J.-F. was a recipient of a H.C. Ørsted COFUND Postdoc Fellowship from the Technical University of Denmark.

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Halfon, Y., Jimenez-Fernandez, A., La Rosa, R., Portero, R. E., Johansen, H. K., Matzov, D., Eyal, Z., Bashan, A., Zimmerman, E., Belousoff, M., Molin, S., & Yonath, A. (2019). Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate. Proceedings of the National Academy of Sciences of the United States of America, 116(44), 22275-22281. https://doi.org/10.1073/pnas.1909831116

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abstract = "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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Halfon, Y, Jimenez-Fernandez, A, La Rosa, R, Portero, RE, Johansen, HK, Matzov, D, Eyal, Z , Bashan, A, Zimmerman, E, Belousoff, M, Molin, S & Yonath, A 2019, 'Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 44, pp. 22275-22281. https://doi.org/10.1073/pnas.1909831116

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AU - Eyal, Zohar

AU - Bashan, Anat

AU - Zimmerman, Ella

AU - Belousoff, Matthew

AU - Molin, Soren

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Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate

Abstract

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