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Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0001-7802-5572
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).ORCID iD: 0000-0003-4656-3362
Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-7275-5459
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Number of Authors: 72022 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e77460Article in journal (Refereed) Published
Abstract [en]

The mitoribosome regulates cellular energy production, and its dysfunction is associated with aging. Inhibition of the mitoribosome can be caused by off-target binding of antimicrobial drugs and was shown to be coupled with a bilateral decreased visual acuity. Previously, we reported mitochondria-specific protein aspects of the mitoribosome, and in this article we present a 2.4-Å resolution structure of the small subunit in a complex with the anti-tuberculosis drug streptomycin that reveals roles of non-protein components. We found iron–sulfur clusters that are coordinated by different mitoribosomal proteins, nicotinamide adenine dinucleotide (NAD) associated with rRNA insertion, and posttranslational modifications. This is the first evidence of inter-protein coordination of iron–sulfur, and the finding of iron–sulfur clusters and NAD as fundamental building blocks of the mitoribosome directly links to mitochondrial disease and aging. We also report details of streptomycin interactions, suggesting that the mitoribosome-bound streptomycin is likely to be in hydrated gem-diol form and can be subjected to other modifications by the cellular milieu. The presented approach of adding antibiotics to cultured cells can be used to define their native structures in a bound form under more physiological conditions, and since streptomycin is a widely used drug for treatment, the newly resolved features can serve as determinants for targeting.

Place, publisher, year, edition, pages
2022. Vol. 11, article id e77460
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-213372DOI: 10.7554/eLife.77460ISI: 000895763900001PubMedID: 36480258Scopus ID: 2-s2.0-85143564523OAI: oai:DiVA.org:su-213372DiVA, id: diva2:1724801
Available from: 2023-01-09 Created: 2023-01-09 Last updated: 2023-03-16Bibliographically approved
In thesis
1. Structural investigation of human mitochondrial translation and off-target antibiotic binding
Open this publication in new window or tab >>Structural investigation of human mitochondrial translation and off-target antibiotic binding
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human mitochondrial translation machinery has evolved to translate 13 mitochondrial mRNAs encoding components of the oxidative phosphorylation pathway responsible for ATP production. The structural basis of human mitochondrial translation is distinct from the canonical bacterial and cytosolic translation systems. Further, mutations affecting mitochondrial protein synthesis disrupt ATP production resulting in myopathies and neurodegenerative diseases. Structural studies have identified the core components of the human mitoribosome and some of its associated translation factors but several important aspects such as the role of mito-specific proteins in translation, rRNA modifications, composition of its ultrastructure including ions, small molecule co-factors, and solvent content, remain poorly understood. Importantly, several important antibiotics that target bacterial translation also affect mitochondrial translation, thereby causing adverse effects in patients. Understanding the mechanism of off-target antibiotic binding to the mitoribosome could help in designing better antibiotics. In this work, we use electron cryo-microscopy to determine the structures of the human mitoribosome in complex with ligands: mRNA/tRNA and translation activators such as LRPPRC-SLIRP. This allows us to explore the structural basis of mitochondrial translation, identifying the roles of mito-specific protein elements in tRNA and mRNA binding and recruitment (Papers 1 and 2). We determine a 2.2 Å resolution structure of the human mitoribosome and a 2.4 Å resolution structure of the mitoribosomal small subunit in complex with the tuberculosis drug, streptomycin. Together, the structures represent the most detailed and complete models for the human mitoribosome, revealing rRNA and protein modifications; several novel small molecule cofactors: 2Fe-2S clusters, polyamines and nucleotides and mechanisms of antibiotic binding (Papers 3 and 4).

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2023. p. 65
Keywords
Mitochondrial translation, mitoribosome, electron cryo-microscopy, LRPPRC-SLIRP, antibiotics, streptomycin
National Category
Structural Biology Biophysics Biochemistry and Molecular Biology
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-215504 (URN)978-91-8014-240-3 (ISBN)978-91-8014-241-0 (ISBN)
Public defence
2023-04-24, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (English)
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Available from: 2023-03-30 Created: 2023-03-16 Last updated: 2023-03-24Bibliographically approved

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Itoh, YuzuruSingh, VivekNaschberger, AndreasAmunts, Alexey

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