The ZN domain acts as a dynamic switch coordinating multiple-step aminoacylation in bacterial leucyl-tRNA synthetase
Abstract
Aminoacyl-tRNA synthetases (AARSs) safeguard translational fidelity by coordinating amino acid activation and tRNA charging within distinct catalytic and editing domains. In leucyl-tRNA synthetase (LeuRS), the small, centrally located zinc-binding domain (ZN domain) sits at the crossroads of these functional centres, yet its role has remained enigmatic. Here, we present crystal structures of the Escherichia coli LeuRS-tRNALeu complex that capture the ZN domain in a previously unobserved conformation, revealing the pre-activation state. By integrating structural data with kinetic analysis, we propose a model for the aminoacylation reaction in which the ZN domain functions as a dynamic molecular switch that coordinates the different catalytic steps of the reaction cycle. We show that the ZN domain first acts as a wedge to prime the synthetic active site while locking the 3'-end tRNALeu in the editing domain. It subsequently reorients to stabilize the tRNA acceptor stem for aminoacyl transfer, before releasing it for proofreading. These findings resolve the mechanism of long-range domain communication in LeuRS and identify a discrete, druggable intermediate for the design of next-generation antimicrobials.
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BibTeX
@article{hoffmann2026domain,
title = {{The ZN domain acts as a dynamic switch coordinating multiple-step aminoacylation in bacterial leucyl-tRNA synthetase}},
author = {Guillaume Hoffmann and Morana Dulić and Ita Gruic-Sovulj and Andrés Palencia},
journal = {Nucleic Acids Research},
year = {2026},
month = aug,
doi = {10.1093/nar/gkag786},
url = {https://hal.science/hal-05771703v1},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - The ZN domain acts as a dynamic switch coordinating multiple-step aminoacylation in bacterial leucyl-tRNA synthetase
AU - Guillaume Hoffmann
AU - Morana Dulić
AU - Ita Gruic-Sovulj
AU - Andrés Palencia
PY - 2026
DA - 2026/08/27
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag786
UR - https://hal.science/hal-05771703v1
AB - Aminoacyl-tRNA synthetases (AARSs) safeguard translational fidelity by coordinating amino acid activation and tRNA charging within distinct catalytic and editing domains. In leucyl-tRNA synthetase (LeuRS), the small, centrally located zinc-binding domain (ZN domain) sits at the crossroads of these functional centres, yet its role has remained enigmatic. Here, we present crystal structures of the Escherichia coli LeuRS-tRNALeu complex that capture the ZN domain in a previously unobserved conformation, revealing the pre-activation state. By integrating structural data with kinetic analysis, we propose a model for the aminoacylation reaction in which the ZN domain functions as a dynamic molecular switch that coordinates the different catalytic steps of the reaction cycle. We show that the ZN domain first acts as a wedge to prime the synthetic active site while locking the 3'-end tRNALeu in the editing domain. It subsequently reorients to stabilize the tRNA acceptor stem for aminoacyl transfer, before releasing it for proofreading. These findings resolve the mechanism of long-range domain communication in LeuRS and identify a discrete, druggable intermediate for the design of next-generation antimicrobials.
SN - 0305-1048
SN - 1362-4962
ER -