5XE3

Endoribonuclease in complex with its cognate antitoxin from Mycobacterial species

Summary for 5XE3

• Entry DOI: 10.2210/pdb5xe3/pdb
• Related: 5XE2
• Descriptor: Endoribonuclease MazF4, Probable antitoxin MazE4 (3 entities in total)
• Functional Keywords: endonuclease, hydrolase-antitoxin complex, hydrolase/antitoxin
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 6
• Total formula weight: 65211.37

Authors

Ahn, D.-H.,Lee, K.-Y.,Lee, S.J.,Yoon, H.J.,Kim, S.-J.,Lee, B.-J. (deposition date: 2017-03-31, release date: 2017-10-11, Last modification date: 2023-11-22)

Primary citation

Ahn, D.H.,Lee, K.Y.,Lee, S.J.,Park, S.J.,Yoon, H.J.,Kim, S.J.,Lee, B.J.
Structural analyses of the MazEF4 toxin-antitoxin pair in Mycobacterium tuberculosis provide evidence for a unique extracellular death factor.
J. Biol. Chem., 292:18832-18847, 2017

PubMed Abstract: The bacterial toxin-antitoxin MazEF system in the tuberculosis (TB)-causing bacterium is activated under unfavorable conditions, including starvation, antibiotic exposure, and oxidative stress. This system contains the ribonucleolytic enzyme MazF and has emerged as a promising drug target for TB treatments targeting the latent stage of infection and reportedly mediates a cell death process via a peptide called extracellular death factor (EDF). Although it is well established that the increase in EDF-mediated toxicity of MazF drives a cell-killing phenomenon, the molecular details are poorly understood. Moreover, the divergence in sequences among reported EDFs suggests that each bacterial species has a unique EDF. To address these open questions, we report here the structures of MazF4 and MazEF4 complexes from , representing the first MazEF structures from this organism. We found that MazF4 possesses a negatively charged MazE4-binding pocket in contrast to the positively charged MazE-binding pockets in homologous MazEF complex structures from other bacteria. Moreover, using NMR spectroscopy and biochemical assays, we unraveled the molecular interactions of MazF4 with its RNA substrate and with a new EDF homolog originating from The EDF homolog discovered here possesses a positively charged residue at the C terminus, making this EDF distinct from previously reported EDFs. Overall, our results suggest that evolved a unique MazF and EDF and that the distinctive EDF sequence could serve as a starting point for designing new anti-tuberculosis drugs. We therefore conclude that this study might contribute to the development of a new line of anti-tuberculosis agents.

PubMed: 28972145
DOI: 10.1074/jbc.M117.807974

Experimental method

X-RAY DIFFRACTION (2.3 Å)