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  Inhibition of translation initiation complex formation by GE81112 unravels a 16S rRNA structural switch involved in P-site decoding.

Fabbretti, A., Schedlbauer, A., Brandi, L., Kaminishi, T., Giuliodori, A. M., Garofalo, R., et al. (2016). Inhibition of translation initiation complex formation by GE81112 unravels a 16S rRNA structural switch involved in P-site decoding. Proceedings of the National Academy of Sciences of the United States of America, 113(16), E2286-E2295. doi:10.1073/pnas.1521156113.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-5C00-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-A501-2
Genre: Journal Article

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 Creators:
Fabbretti, A., Author
Schedlbauer, A., Author
Brandi, L., Author
Kaminishi, T., Author
Giuliodori, A. M., Author
Garofalo, R.1, Author              
Ochoa-Lizarralde, B., Author
Takemoto, C., Author
Yokoyama, S., Author
Connell, S. R., Author
Gualerzi, C. O., Author
Fucini, P., Author
Affiliations:
1Department of Physical Biochemistry, MPI for Biophysical Chemistry, Max Planck Society, ou_578598              

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Free keywords: GE81112; ribosome; X-ray crystallography; protein synthesis; antibiotics
 Abstract: In prokaryotic systems, the initiation phase of protein synthesis is governed by the presence of initiation factors that guide the transition of the small ribosomal subunit (30S) from an unlocked preinitiation complex (30S preIC) to a locked initiation complex (30SIC) upon the formation of a correct codon-anticodon interaction in the peptidyl (P) site. Biochemical and structural characterization of GE81112, a translational inhibitor specific for the initiation phase, indicates that the main mechanism of action of this antibiotic is to prevent P-site decoding by stabilizing the anticodon stem loop of the initiator tRNA in a distorted conformation. This distortion stalls initiation in the unlocked 30S preIC state characterized by tighter IF3 binding and a reduced association rate for the 50S subunit. At the structural level we observe that in the presence of GE81112 the h44/h45/h24a interface, which is part of the IF3 binding site and forms ribosomal intersubunit bridges, preferentially adopts a disengaged conformation. Accordingly, the findings reveal that the dynamic equilibrium between the disengaged and engaged conformations of the h44/h45/h24a interface regulates the progression of protein synthesis, acting as a molecular switch that senses and couples the 30S P-site decoding step of translation initiation to the transition from an unlocked preIC to a locked 30SIC state.

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Language(s): eng - English
 Dates: 2016-04-19
 Publication Status: Published online
 Pages: -
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 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1521156113
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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 113 (16) Sequence Number: - Start / End Page: E2286 - E2295 Identifier: -