8RRI
Human mitochondrial ribosome in complex with antibiotic tigecycline
This is a non-PDB format compatible entry.
Summary for 8RRI
| Entry DOI | 10.2210/pdb8rri/pdb |
| EMDB information | 19460 19526 19544 |
| Descriptor | mitochondrial tRNAVal, 39S ribosomal protein L16, mitochondrial, 39S ribosomal protein L17, mitochondrial, ... (94 entities in total) |
| Functional Keywords | antibiotics; immunometabolism; mitochondrial ribosomes; tetracyclines; t cells., ribosome |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 86 |
| Total formula weight | 2944819.76 |
| Authors | Khawaja, A.,Sing, V.,Nguyen, M.D.,Rorbach, J. (deposition date: 2024-01-22, release date: 2025-03-12, Last modification date: 2025-05-14) |
| Primary citation | Shao, Q.,Khawaja, A.,Nguyen, M.D.,Singh, V.,Zhang, J.,Liu, Y.,Nordin, J.,Adori, M.,Axel Innis, C.,Castro Dopico, X.,Rorbach, J. T cell toxicity induced by tigecycline binding to the mitochondrial ribosome. Nat Commun, 16:4080-4080, 2025 Cited by PubMed Abstract: Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5-10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design. PubMed: 40312422DOI: 10.1038/s41467-025-59388-9 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.4 Å) |
Structure validation
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