Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules
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-sp...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/77460 |
| _version_ | 1811206096141942784 |
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| author | Yuzuru Itoh Vivek Singh Anas Khawaja Andreas Naschberger Minh Duc Nguyen Joanna Rorbach Alexey Amunts |
| author_facet | Yuzuru Itoh Vivek Singh Anas Khawaja Andreas Naschberger Minh Duc Nguyen Joanna Rorbach Alexey Amunts |
| author_sort | Yuzuru Itoh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T03:41:01Z |
| format | Article |
| id | doaj.art-71e26c92444548e79d73d278270bfc82 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T03:41:01Z |
| publishDate | 2022-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-71e26c92444548e79d73d278270bfc822022-12-22T03:49:16ZengeLife Sciences Publications LtdeLife2050-084X2022-12-011110.7554/eLife.77460Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological moleculesYuzuru Itoh0Vivek Singh1https://orcid.org/0000-0003-4656-3362Anas Khawaja2https://orcid.org/0000-0002-9721-7454Andreas Naschberger3Minh Duc Nguyen4https://orcid.org/0000-0003-2945-9707Joanna Rorbach5https://orcid.org/0000-0002-2891-2840Alexey Amunts6https://orcid.org/0000-0002-5302-1740Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SwedenScience for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SwedenDepartment of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, SwedenScience for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SwedenDepartment of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, SwedenDepartment of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Karolinska Institutet, Stockholm, SwedenScience for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, SwedenThe 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.https://elifesciences.org/articles/77460mitochondriamitoribosomeantibioticstranslationFe–S clusteraging |
| spellingShingle | Yuzuru Itoh Vivek Singh Anas Khawaja Andreas Naschberger Minh Duc Nguyen Joanna Rorbach Alexey Amunts Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules eLife mitochondria mitoribosome antibiotics translation Fe–S cluster aging |
| title | Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules |
| title_full | Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules |
| title_fullStr | Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules |
| title_full_unstemmed | Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules |
| title_short | Structure of the mitoribosomal small subunit with streptomycin reveals Fe-S clusters and physiological molecules |
| title_sort | structure of the mitoribosomal small subunit with streptomycin reveals fe s clusters and physiological molecules |
| topic | mitochondria mitoribosome antibiotics translation Fe–S cluster aging |
| url | https://elifesciences.org/articles/77460 |
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