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

The 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 (1)(1–3). TRL1 is an essential component of pre-tRNA splicing and the processing of the Ire1p (“Inositol-requiring enzyme 1″) dependent non-canonical splicing of the mRNA coding for HAC-1 (“Homologous to 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 non-covalently linked 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.