The present study endeavors to decode the details of the transcriptional autoregulation effected by the MazE9 antitoxin of the Mycobacterium tuberculosis MazEF9 toxin-antitoxin system. Regulation of this bicistronic operon at the level of transcription is a critical biochemical process that is key for the organism's stress adaptation and virulence. Here, we have reported the solution structure of the DNA binding domain of MazE9 and scrutinized the thermodynamic and kinetic parameters operational in its interaction with the promoter/operator region, specific to the mazEF9 operon. A HADDOCK model of MazE9 bound to its operator DNA has been calculated based on the information on interacting residues obtained from these studies. The thermodynamics and kinetics of the interaction of MazE9 with the functionally related mazEF6 operon indicate that the potential for intracellular cross-regulation is unlikely. An interesting feature of MazE9 is the cis ⇌ trans conformational isomerization of proline residues in the intrinsically disordered C-terminal domain of this antitoxin.
Keywords: DNA binding; Mycobacterium tuberculosis; NMR spectroscopy; conformational dynamics; proline cis-trans isomerization; protein structure; ribbon-helix-helix (RHH) motif; toxin-antitoxin system; transcription factor.
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