Deciphering the conformational stability of MazE7 antitoxin in Mycobacterium tuberculosis from molecular dynamics simulation study
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Rituparna Saha1, Gourab Bhattacharje1, Soumya De2
1Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India.
Abstract:
MazEF Toxin-antitoxin (TA) systems are associated with the persistent phenotype of the pathogen, Mycobacterium tuberculosis (Mtb), aiding their survival. Though extensively studied, the mode of action between the antitoxin-toxin and DNA of this family remains largely unclear. Here, the important interactions between MazF7 toxin and MazE7 antitoxin, and how MazE7 binds its promoter/operator region have been studied. To elucidate this, molecular dynamics (MD) simulation has been performed on MazE7, MazF7, MazEF7, MazEF7-DNA, and MazE7-DNA complexes to investigate how MazF7 and DNA affect the conformational change and dynamics of MazE7 antitoxin. This study demonstrated that the MazE7 dimer is disordered and one monomer (Chain C) attains stability after binding to the MazF7 toxin. Both the monomers (Chain C and Chain D) however are stabilized when MazE7 binds to DNA. MazE7 is also observed to sterically inhibit tRNA from binding to MazF7, thus suppressing its toxic activity. Comparative structural analysis performed on all the available antitoxins/antitoxin-toxin-DNA structures revealed MazEF7-DNA mechanism was similar to another TA system, AtaRT_E.coli. Simulation performed on the crystal structures of AtaR, AtaT, AtaRT, AtaRT-DNA, and AtaR-DNA showed that the disordered AtaR antitoxin attains stability by AtaT and DNA binding similar to MazE7. Based on these analyses it can thus be hypothesized that the disordered antitoxins enable tighter toxin and DNA binding thus preventing accidental toxin activation. Overall, this study provides crucial structural and dynamic insights into the MazEF7 toxin-antitoxin system and should provide a basis for targeting this TA system in combating Mycobacterium tuberculosis.Communicated by Ramaswamy H. Sarma.
Insights
MazEF toxin-antitoxin systems help Mycobacterium tuberculosis survive. This study reveals how MazE7 antitoxin stabilizes by binding MazF7 toxin and DNA, inhibiting toxicity and offering new therapeutic targets.
Area of Science:
- Microbiology
- Structural Biology
- Biochemistry
Background:
- MazEF toxin-antitoxin (TA) systems are crucial for Mycobacterium tuberculosis (Mtb) persistence.
- The precise interactions between MazEF antitoxins, toxins, and DNA remain largely uncharacterized.
Purpose of the Study:
- To investigate the structural and dynamic interactions within the MazEF7 toxin-antitoxin system.
- To elucidate how MazE7 antitoxin interacts with MazF7 toxin and DNA.
Main Methods:
- Molecular dynamics (MD) simulations were performed on various MazEF7 complexes (antitoxin, toxin, toxin-antitoxin, and DNA-bound forms).
- Comparative structural analysis was conducted with other TA systems, such as AtaRT from E. coli.
Main Results:
- The MazE7 antitoxin dimer is inherently disordered, gaining stability upon binding to MazF7 toxin.
- Both MazE7 monomers are stabilized when bound to DNA.
- MazE7 sterically inhibits tRNA binding to MazF7, thereby suppressing toxicity.
- The MazEF7-DNA interaction mechanism mirrors that of the AtaRT system.
Conclusions:
- Disordered antitoxins may facilitate tighter binding to both toxins and DNA, preventing premature toxin activation.
- The findings offer critical structural and dynamic insights into the MazEF7 TA system.
- This research provides a foundation for developing novel therapeutic strategies targeting TA systems in Mtb.
