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A nucleotidyltransferase toxin inhibits growth of Mycobacterium tuberculosis through inactivation of tRNA acceptor stems

DOI: 10.1126/sciadv.abb6651 DOI Help

Authors: Yiming Cai (Université de Toulouse, CNRS) , Ben Usher (Durham University) , Claude Gutierrez (Université de Toulouse, CNRS) , Anastasia Tolcan (UMR8261 (CNRS, Université de Paris) , Moise Mansour (Université de Toulouse, CNRS) , Peter C. Fineran (University of Otago) , Ciarán Condon (UMR8261 (CNRS, Université de Paris)) , Olivier Neyrolles (Université de Toulouse, CNRS) , Pierre Genevaux (Université de Toulouse, CNRS) , Tim R. Blower (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 6

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 18598

Open Access Open Access

Abstract: Toxin-antitoxin systems are widespread stress-responsive elements, many of whose functions remain largely unknown. Here, we characterize the four DUF1814-family nucleotidyltransferase-like toxins (MenT1–4) encoded by the human pathogen Mycobacterium tuberculosis. Toxin MenT3 inhibited growth of M. tuberculosis when not antagonized by its cognate antitoxin, MenA3. We solved the structures of toxins MenT3 and MenT4 to 1.6 and 1.2 Å resolution, respectively, and identified the biochemical activity and target of MenT3. MenT3 blocked in vitro protein expression and prevented tRNA charging in vivo. MenT3 added pyrimidines (C or U) to the 3′-CCA acceptor stems of uncharged tRNAs and exhibited strong substrate specificity in vitro, preferentially targeting tRNASer from among the 45 M. tuberculosis tRNAs. Our study identifies a previously unknown mechanism that expands the range of enzymatic activities used by bacterial toxins, uncovering a new way to block protein synthesis and potentially treat tuberculosis and other infections.

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 05/08/2020 09:03

Documents:
eabb6651.full.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)