Publication Date:
2014-09-12
Description:
The ribosome is a molecular machine responsible for protein synthesis and a major target for small-molecule inhibitors. Compared to the wealth of structural information available on ribosome-targeting antibiotics in bacteria, our understanding of the binding mode of ribosome inhibitors in eukaryotes is currently limited. Here we used X-ray crystallography to determine 16 high-resolution structures of 80S ribosomes from Saccharomyces cerevisiae in complexes with 12 eukaryote-specific and 4 broad-spectrum inhibitors. All inhibitors were found associated with messenger RNA and transfer RNA binding sites. In combination with kinetic experiments, the structures suggest a model for the action of cycloheximide and lactimidomycin, which explains why lactimidomycin, the larger compound, specifically targets the first elongation cycle. The study defines common principles of targeting and resistance, provides insights into translation inhibitor mode of action and reveals the structural determinants responsible for species selectivity which could guide future drug development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garreau de Loubresse, Nicolas -- Prokhorova, Irina -- Holtkamp, Wolf -- Rodnina, Marina V -- Yusupova, Gulnara -- Yusupov, Marat -- 294312/European Research Council/International -- England -- Nature. 2014 Sep 25;513(7519):517-22. doi: 10.1038/nature13737. Epub 2014 Sep 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Universite de Strasbourg, 67404, Illkirch, France. ; Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25209664" target="_blank"〉PubMed〈/a〉
Keywords:
Base Sequence
;
Binding Sites/drug effects
;
Crystallography, X-Ray
;
Cycloheximide/pharmacology
;
Drug Resistance/drug effects
;
Eukaryotic Cells/*chemistry/drug effects/enzymology
;
Kinetics
;
Macrolides/pharmacology
;
Models, Molecular
;
Molecular Targeted Therapy
;
Molecular Weight
;
Peptide Chain Elongation, Translational/drug effects
;
Peptidyl Transferases/chemistry/metabolism
;
Piperidones/pharmacology
;
Protein Synthesis Inhibitors/*chemistry/*pharmacology
;
RNA, Messenger/genetics/metabolism
;
RNA, Transfer/genetics/metabolism
;
Ribosome Subunits, Large, Eukaryotic/chemistry/drug effects/metabolism
;
Ribosomes/*chemistry/*drug effects/metabolism
;
Saccharomyces cerevisiae/*chemistry
;
Species Specificity
;
Substrate Specificity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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