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tRNA dissociation from EF-Tu after GTP hydrolysis: Primary steps and antibiotic inhibition.

MPS-Authors
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Warias,  M.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Grubmüller,  H.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Bock,  L. V.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Citation

Warias, M., Grubmüller, H., & Bock, L. V. (2020). tRNA dissociation from EF-Tu after GTP hydrolysis: Primary steps and antibiotic inhibition. Biophysical Journal, 118(1), 151-161. doi:10.1016/j.bpj.2019.10.028.


Cite as: http://hdl.handle.net/21.11116/0000-0005-452A-F
Abstract
In each round of ribosomal translation, the translational GTPase elongation factor Tu (EF-Tu) delivers a transfer RNA (tRNA) to the ribosome. After successful decoding, EF-Tu hydrolyzes 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.