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- Title
Characterization of benzoxaborole-based antifungal resistance mutations demonstrates that editing depends on electrostatic stabilization of the leucyl-tRNA synthetase editing cap
- Authors
Sarkar, Jaya; Mao, Weimin; Lincecum, Tommie L.; Alley, M.R.K.; Martinis, Susan A.
- Abstract
Abstract: The broad-spectrum benzoxaborole antifungal AN2690 blocks protein synthesis by inhibiting leucyl-tRNA synthetase (LeuRS) via a novel oxaborole tRNA trapping mechanism in the editing site. Herein, one set of resistance mutations is at Asp487 outside the LeuRS hydrolytic editing pocket, in a region of unknown function. It is located within a eukaryote/archaea specific insert I4, which forms part of a cap over a benzoxaborole-AMP that is bound in the LeuRS CP1 domain editing active site. Mutational and biochemical analysis at Asp487 identified a salt bridge between Asp487 and Arg316 in the hinge region of the I4 cap of yeast LeuRS that is critical for tRNA deacylation. We hypothesize that this electrostatic interaction stabilizes the cap during binding of the editing substrate for hydrolysis.
- Subjects
ANTIFUNGAL agents; GENETIC mutation; DRUG resistance; LYSYL-tRNA synthetase; PROTEIN synthesis; GENETIC translation; BINDING sites
- Publication
FEBS Letters, 2011, Vol 585, Issue 19, p2986
- ISSN
0014-5793
- Publication type
Article
- DOI
10.1016/j.febslet.2011.08.010