Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin

Moran Shalev-Benami (), Yan Zhang, Haim Rozenberg, Yuko Nobe, Masato Taoka, Donna Matzov, Ella Zimmerman, Anat Bashan, Toshiaki Isobe, Charles L. Jaffe, Ada Yonath () and Georgios Skiniotis ()
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Moran Shalev-Benami: Weizmann Institute of Science
Yan Zhang: Stanford University School of Medicine
Haim Rozenberg: Weizmann Institute of Science
Yuko Nobe: Tokyo Metropolitan University
Masato Taoka: Tokyo Metropolitan University
Donna Matzov: Weizmann Institute of Science
Ella Zimmerman: Weizmann Institute of Science
Anat Bashan: Weizmann Institute of Science
Toshiaki Isobe: Tokyo Metropolitan University
Charles L. Jaffe: Hebrew University-Hadassah Medical School
Ada Yonath: Weizmann Institute of Science
Georgios Skiniotis: Stanford University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01664-4

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