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Decoding the Structure–Function Relationship of the Muramidase Domain in E. Coli O157.H7 Bacteriophage Endolysin: A Potential Building Block for Chimeric Enzybiotics Publisher



Javid M1 ; Shahverdi AR1 ; Ghasemi A4 ; Moosavimovahedi AA4 ; Ebrahimhabibi A1 ; Sepehrizadeh Z1
Authors
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Authors Affiliations
  1. 1. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy & amp
  2. 2. Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran
  3. 3. Biosensor Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

Source: Protein Journal Published:2024


Abstract

Bacteriophage endolysins are potential alternatives to conventional antibiotics for treating multidrug-resistant gram-negative bacterial infections. However, their structure–function relationships are poorly understood, hindering their optimization and application. In this study, we focused on the individual functionality of the C-terminal muramidase domain of Gp127, a modular endolysin from E. coli O157:H7 bacteriophage PhaxI. This domain is responsible for the enzymatic activity, whereas the N-terminal domain binds to the bacterial cell wall. Through protein modeling, docking experiments, and molecular dynamics simulations, we investigated the activity, stability, and interactions of the isolated C-terminal domain with its ligand. We also assessed its expression, solubility, toxicity, and lytic activity using the experimental data. Our results revealed that the C-terminal domain exhibits high activity and toxicity when tested individually, and its expression is regulated in different hosts to prevent self-destruction. Furthermore, we validated the muralytic activity of the purified refolded protein by zymography and standardized assays. These findings challenge the need for the N-terminal binding domain to arrange the active site and adjust the gap between crucial residues for peptidoglycan cleavage. Our study shed light on the three-dimensional structure and functionality of muramidase endolysins, thereby enriching the existing knowledge pool and laying a foundation for accurate in silico modeling and the informed design of next-generation enzybiotic treatments. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
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