Elongation Factor Tu Switch I Element is a Gate for Aminoacyl-tRNA Selection.

Selection of correct aminoacyl (aa)-tRNA at the ribosomal A site is fundamental to maintaining translational fidelity. Aa-tRNA selection is a multistep process facilitated by the guanosine triphosphatase elongation factor (EF)-Tu. EF-Tu delivers aa-tRNA to the ribosomal A site and participates in tRNA selection. The structural mechanism of how EF-Tu is involved in proofreading remains to be fully resolved. Here, we provide evidence that switch I of EF-Tu facilitates EF-Tu's involvement during aa-tRNA selection. Using structure-based and explicit solvent molecular dynamics simulations based on recent cryo-electron microscopy reconstructions, we studied the conformational change of EF-Tu from the guanosine triphosphate to guanine diphosphate conformation during aa-tRNA accommodation. Switch I of EF-Tu rapidly converts from an α-helix into a β-hairpin and moves to interact with the acceptor stem of the aa-tRNA. In doing so, switch I gates the movement of the aa-tRNA during accommodation through steric interactions with the acceptor stem. Pharmacological inhibition of the aa-tRNA accommodation pathway prevents the proper positioning of switch I with the aa-tRNA acceptor stem, suggesting that the observed interactions are specific for cognate aa-tRNA substrates, and thus capable of contributing to the fidelity mechanism.

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