替加环素广泛用于治疗没有有效药物的复杂细菌感染。它通过阻断核糖体A位点来抑制细菌蛋白质翻译。然而,尽管它对人类细胞也有细胞毒性,其抑制的分子机制尚不清楚。这里,我们提出了替加环素结合的人线粒体55S的冷冻EM结构,39S,细胞质80S和酵母细胞质80S核糖体。我们发现在临床相关浓度下,替加环素有效靶向人55Smitoribosomes,潜在的,通过阻碍A位点tRNA调节和阻断肽基转移中心。相比之下,替加环素在生理浓度下不与人80S核糖体结合。然而,在高浓度的替加环素下,除了封锁A-site,人和酵母80S核糖体都在限制L1茎运动的另一个保守结合位点结合替加环素。总之,观察到的替加环素独特的结合特性可以指导药物设计和治疗的新途径。
Tigecycline 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.