Structural basis for the inhibition of the eukaryotic ribosome

被引:403
作者
de Loubresse, Nicolas Garreau [1 ]
Prokhorova, Irina [1 ]
Holtkamp, Wolf [2 ]
Rodnina, Marina V. [2 ]
Yusupova, Gulnara [1 ]
Yusupov, Marat [1 ]
机构
[1] Univ Strasbourg, CNRS, IGBMC, INSERM,U964,UMR7104, F-67404 Illkirch Graffenstaden, France
[2] Max Planck Inst Biophys Chem, Dept Phys Biochem, D-37077 Gottingen, Germany
基金
欧洲研究理事会;
关键词
PROTEIN-SYNTHESIS; AMINOGLYCOSIDE ANTIBIOTICS; SACCHAROMYCES-CEREVISIAE; TRANSFER-RNA; CRYPTOPLEURINE RESISTANCE; TRANSLATION INITIATION; CRYSTAL-STRUCTURE; BLASTICIDIN S; YEAST; CELLS;
D O I
10.1038/nature13737
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:517 / +
页数:17
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