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tRNA dissociation from EF-Tu after GTP hydrolysis and Pi release: primary steps and antibiotic inhibition

Malte Warias, View ORCID ProfileHelmut Grubmüller, View ORCID ProfileLars V. Bock
doi: https://doi.org/10.1101/602383
Malte Warias
1Theoretical and Computational Biophysics, MPI for Biophysical Chemistry
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Helmut Grubmüller
1Theoretical and Computational Biophysics, MPI for Biophysical Chemistry
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  • ORCID record for Helmut Grubmüller
Lars V. Bock
1Theoretical and Computational Biophysics, MPI for Biophysical Chemistry
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  • For correspondence: lbock@gwdg.de
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Abstract

In each round of ribosomal translation, the translational GTPase EF-Tu delivers a tRNA to the ribosome. After successful decoding, EF-Tu hydrolyses GTP, which triggers a conformational change that ultimately results in the release of the tRNA from EF-Tu. To identify the primary steps of these conformational changes and how they are prevented by the antibiotic kirromycin, we employed all-atom explicit-solvent Molecular Dynamics simulations of the full ribosome-EF-Tu complex. Our results suggest that after GTP hydrolysis and Pi release, the loss of interactions between the nucleotide and the switch 1 loop of EF-Tu allows domain D1 of EF-Tu to rotate relative to domains D2 and D3 and leads to an increased flexibility of the switch 1 loop. This rotation induces a closing of the D1-D3 interface and an opening of the D1-D2 interface. We propose that the opening of the D1-D2 interface, which binds the CCA-tail of the tRNA, weakens the crucial EF-Tu-tRNA interactions which lowers tRNA binding affinity, representing the first step of tRNA release. Kirromycin binds within the D1-D3 interface, sterically blocking its closure, but does not prevent hydrolysis. The resulting increased flexibility of switch 1 explains why it is not resolved in kirromycin-bound structures.

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Posted April 11, 2019.
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tRNA dissociation from EF-Tu after GTP hydrolysis and Pi release: primary steps and antibiotic inhibition
Malte Warias, Helmut Grubmüller, Lars V. Bock
bioRxiv 602383; doi: https://doi.org/10.1101/602383
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tRNA dissociation from EF-Tu after GTP hydrolysis and Pi release: primary steps and antibiotic inhibition
Malte Warias, Helmut Grubmüller, Lars V. Bock
bioRxiv 602383; doi: https://doi.org/10.1101/602383

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