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TitleAtomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin.
Journal, issue, pagesNat Commun, Vol. 8, Issue 1, Page 1589, Year 2017
Publish dateNov 17, 2017
AuthorsMoran 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 AbstractLeishmania 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 linksNat Commun / PubMed:29150609 / PubMed Central
MethodsEM (single particle)
Resolution2.5 - 2.7 Å
Structure data

7024

6az1

EMDB-7024, PDB-6az1:
Cryo-EM structure of the small subunit of Leishmania ribosome bound to paromomycin
Method: EM (single particle) / Resolution: 2.7 Å

7025

6az3

EMDB-7025, PDB-6az3:
Cryo-EM structure of of the large subunit of Leishmania ribosome bound to paromomycin
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-PAR:
PAROMOMYCIN / Antimicrobial, medication*YM / Paromomycin

ChemComp-HOH:
WATER / Water

Source
  • leishmania donovani (eukaryote)
  • escherichia coli (E. coli)
KeywordsRIBOSOME/ANTIBIOTIC / Leishmania donovani / ribosome / aminoglycoside / paromomycin / RIBOSOME-ANTIBIOTIC complex / Leishmania

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