Faculty of Chemistry, Department of Structural Biology, Weizmann Institute of Science, Rehovot, 761001, Israel.
Departments of Molecular and Cellular Physiology, and Structural Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nat Commun. 2017 Nov 17;8(1):1589. doi: 10.1038/s41467-017-01664-4.
Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite's cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of the Leishmania ribosome in complex with paromomycin (PAR), a highly potent compound recently approved for treatment of the fatal visceral leishmaniasis (VL). The structure reveals the mechanism by which the drug induces its deleterious effects on the parasite. We further show that PAR interferes with several aspects of cytosolic translation, thus highlighting the cytosolic rather than the mitochondrial ribosome as the primary drug target. The results also highlight unique as well as conserved elements in the PAR-binding pocket that can serve as hotspots for the development of novel therapeutics.
利什曼原虫是一种单细胞真核寄生虫，感染了全球数百万人，目前的治疗方法仅限于少数几种药物，这些药物主要针对寄生虫细胞包膜中的元素。在这里，我们确定了与帕罗霉素（PAR）复合的利什曼核糖体的原子分辨率电子冷冻电镜（cryo-EM）结构，PAR 是一种最近被批准用于治疗致命内脏利什曼病（VL）的高活性化合物。该结构揭示了药物对寄生虫产生有害影响的机制。我们进一步表明，PAR 干扰了细胞质翻译的几个方面，因此突出了细胞质核糖体而不是线粒体核糖体作为主要的药物靶点。研究结果还突出了 PAR 结合口袋中独特且保守的元素，这些元素可以作为开发新型治疗药物的热点。
