8xt2
Cryo-EM structure of the human 55S mitoribosome with 10uM Tigecycline
Structural highlights
FunctionRM41_HUMAN Component of the mitochondrial ribosome large subunit. Also involved in apoptosis and cell cycle. Enhances p53/TP53 stability, thereby contributing to p53/TP53-induced apoptosis in response to growth-inhibitory condition. Enhances p53/TP53 translocation to the mitochondria. Has the ability to arrest the cell cycle at the G1 phase, possibly by stabilizing the CDKN1A and CDKN1B (p27Kip1) proteins.[1] [2] Publication Abstract from PubMedTigecycline is widely used for treating complicated bacterial infections for which there are no effective drugs. It inhibits bacterial protein translation by blocking the ribosomal A-site. However, even though it is also cytotoxic for human cells, the molecular mechanism of its inhibition remains unclear. Here, we present cryo-EM structures of tigecycline-bound human mitochondrial 55S, 39S, cytoplasmic 80S and yeast cytoplasmic 80S ribosomes. We find that at clinically relevant concentrations, tigecycline effectively targets human 55S mitoribosomes, potentially, by hindering A-site tRNA accommodation and by blocking the peptidyl transfer center. In contrast, tigecycline does not bind to human 80S ribosomes under physiological concentrations. However, at high tigecycline concentrations, in addition to blocking the A-site, both human and yeast 80S ribosomes bind tigecycline at another conserved binding site restricting the movement of the L1 stalk. In conclusion, the observed distinct binding properties of tigecycline may guide new pathways for drug design and therapy. Structural basis for differential inhibition of eukaryotic ribosomes by tigecycline.,Li X, Wang M, Denk T, Buschauer R, Li Y, Beckmann R, Cheng J Nat Commun. 2024 Jun 28;15(1):5481. doi: 10.1038/s41467-024-49797-7. PMID:38942792[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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