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  Structural basis for the inhibition of the eukaryotic ribosome.

Garreau de Loubresse, N., Prokhorova, I., Holtkamp, W., Rodnina, M. V., Yusupova, G., & Yusupov, M. (2014). Structural basis for the inhibition of the eukaryotic ribosome. Nature, 513(7519), 517-522. doi:10.1038/nature13737.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0023-EE36-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-84C3-3
Genre: Journal Article

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 Creators:
Garreau de Loubresse, N., Author
Prokhorova, I., Author
Holtkamp, W.1, Author              
Rodnina, M. V.1, Author              
Yusupova , G., Author
Yusupov, M., Author
Affiliations:
1Department of Physical Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578598              

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Free keywords: X-ray crystallography; Ribosome; Natural products; Mechanism of action
 Abstract: 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.

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Language(s): eng - English
 Dates: 2014-09-102014-09-25
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/nature13737
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Title: Nature
Source Genre: Journal
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Pages: - Volume / Issue: 513 (7519) Sequence Number: - Start / End Page: 517 - 522 Identifier: -