Mechanistic Insight into the Peptide Binding Modes to Two M. tb MazF Toxins.

Ran Chen,Jie Zhou,Wei Xie

doi:10.3390/toxins13050319

Abstract

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis (M. tb). It is regarded as a major health threat all over the world, mainly because of its high mortality and drug-resistant nature. Toxin-antitoxin (TA) systems are modules ubiquitously found in prokaryotic organisms, and the well-studied MazEF systems (MazE means “what is it?” in Hebrew) are implicated in the formation of “persister cells” in the M. tb pathogen. Here, we report cocrystal structures of M. tb MazF-mt1 and -mt9, two important MazF members responsible for specific mRNA and tRNA cleavages, respectively, in complexes with truncated forms of their cognate antitoxin peptides. These peptides bind to the toxins with comparable affinities to their full-length antitoxins, which would reduce the RNA-cleavage capacities of the toxins in vitro. After structural analysis of the binding modes, we systemically tested the influence of the substitutions of individual residues in the truncated MazE-mt9 peptide on its affinity. This study provides structural insight into the binding modes and the inhibition mechanisms between the MazE/F-mt TA pairs. More importantly, it contributes to the future design of peptide-based antimicrobial agents against TB and potentially relieves the drug-resistance problems by targeting novel M. tb proteins.

Highlights

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis (M.tb)
We showed that the peptides bind to the toxins with comparable affinities to their full-length antitoxins; and this study contributes to the future design of peptide-based antimicrobial agents against TB
The structures of MazF-mt9 in its apo form and in complex with its antitoxin indicated that the antitoxin binds to a highly positively charged interface formed by the MazF-mt9 dimer, which we proposed to coincide with the binding site of tRNA substrates (PDBs 5WYG and 6A6X)

Summary

Introduction

Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis (M. tb). It is transmitted among people and about a quarter of the world’s population is estimated to be infected with this pathogen. Ten million people fall ill annually due to the TB infection around the globe [1]. Without proper treatments, the mortality rate from TB is quite high. TB is the leading cause of death among transmitted diseases, even more lethal than HIV/AIDS. The drug-resistance problem of TB is a formidable challenge to TB care, as it is difficult to treat and takes longer to cure. Despite the global efforts to fight the disease, it continues to be a major public health threat

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Conclusion