Article Dans Une Revue NAR Molecular Medicine Année : 2025

The adaptability of the fungal tRNA ligase’s ATP-binding pocket: a potential target for new antifungal drugs

Résumé

The transfer RNA (tRNA) ligase (TRL1) is a highly conserved multidomain protein that is the archetype of the recently characterized Rnl6 clade. This clade distinguishes itself through a distinct C-terminal domain that sets it apart from other RNA ligase families. TRL1 is an essential component of pre-tRNA splicing and the processing of the Ire1p (Inositol-requiring enzyme 1)-dependent noncanonical splicing of the messenger RNA (mRNA) coding for HAC-1 (Homologous to Activating Transcription Factor / cAMP Response Element-Binding Protein 1 (ATF/CREB1), a transcription factor critical for the unfolded protein response (UPR) in the kingdom of fungi. Here, we report the crystal structure of the N-terminal adenylyl transferase domain (LIG) from Candida glabrata (Nakaseomyces glabratus). The asymmetric unit contained two molecules in complex with noncovalently linked adenosine monophosphate (AMP), revealing conformational differences. In comparison to previous studies, we observe two distinct and partially overlapping ligand-binding pockets, implying new specific residues involved in ligand binding and recognition. These insights on TRL1’s ligand adaptability have important implications for the development of targeted therapies.

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hal-05601368 , version 1 (24-04-2026)

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Alastair G Mcewen, Alessandro Giovinazzo, Pierre Poussin-Courmontagne, Matilde Merolle, Glauco P Tocchini-Valentini, et al.. The adaptability of the fungal tRNA ligase’s ATP-binding pocket: a potential target for new antifungal drugs. NAR Molecular Medicine, 2025, 2 (3), ⟨10.1093/narmme/ugaf028⟩. ⟨hal-05601368⟩
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