Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin

• Published in: Nature communications Vol. 8; no. 1; pp. 1589 - 9
• Main Authors: Shalev-Benami, Moran, Zhang, Yan, Rozenberg, Haim, Nobe, Yuko, Taoka, Masato, Matzov, Donna, Zimmerman, Ella, Bashan, Anat, Isobe, Toshiaki, Jaffe, Charles L., Yonath, Ada, Skiniotis, Georgios
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.11.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/417; 631/337/574/1789; 631/535/1258/1259; 631/92/609; Amino Acid Sequence; Atomic structure; Base Sequence; Binding Sites - genetics; Cryoelectron Microscopy; Cytosol - drug effects; Cytosol - metabolism; Drug development; Drugs; Humanities and Social Sciences; Humans; Leishmania; Leishmania - genetics; Leishmania - metabolism; Leishmania - ultrastructure; Microscopy; Mitochondria; Models, Molecular; multidisciplinary; Parasites; Parasitic diseases; Paromomycin; Paromomycin - chemistry; Paromomycin - metabolism; Paromomycin - pharmacology; Protein Biosynthesis - drug effects; Ribosomal Proteins - chemistry; Ribosomal Proteins - metabolism; Ribosomes - chemistry; Ribosomes - metabolism; Ribosomes - ultrastructure; RNA, Ribosomal - chemistry; RNA, Ribosomal - metabolism; Science; Science (multidisciplinary); Sequence Homology, Amino Acid; Vector-borne diseases; Visceral leishmaniasis
• ISSN: 2041-1723; 2041-1723
• 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. Leishmaniasis is a parasitic disease transmitted by the bite of infected sand flies. Here the authors describe an atomic resolution cryo-EM structure of the Leishmania ribosome in complex with the recently approved drug paromomycin (PAR) and highlight conserved elements in the drug binding pocket that mediate PAR deleterious effects on the parasite.