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Title | Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin. |
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Journal, issue, pages | Nat Commun, Vol. 8, Issue 1, Page 1589, Year 2017 |
Publish date | Nov 17, 2017 |
Authors | Moran Shalev-Benami / Yan Zhang / Haim Rozenberg / Yuko Nobe / Masato Taoka / Donna Matzov / Ella Zimmerman / Anat Bashan / Toshiaki Isobe / Charles L Jaffe / Ada Yonath / Georgios Skiniotis / |
PubMed 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 ...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. |
External links | Nat Commun / PubMed:29150609 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.5 - 2.7 Å |
Structure data | |
Chemicals | ChemComp-MG: ChemComp-PAR: ChemComp-HOH: |
Source |
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Keywords | RIBOSOME/ANTIBIOTIC / Leishmania donovani / ribosome / aminoglycoside / paromomycin / RIBOSOME-ANTIBIOTIC complex / Leishmania |