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Understanding the Molecular Basis for Homodimer Formation of the Pneumococcal Endolysin Cpl-1

ACS Infectious Diseases, ISSN: 2373-8227, Vol: 9, Issue: 5, Page: 1092-1104
2023
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Data on Drug Research Discussed by Researchers at Institute for Bioscience and Biotechnology Research (Understanding the Molecular Basis for Homodimer Formation of the Pneumococcal Endolysin Cpl-1)

2023 JUL 12 (NewsRx) -- By a News Reporter-Staff News Editor at NewsRx Drug Daily -- Data detailed on Drug Research have been presented. According

Article Description

The rise of multi-drug-resistant bacteria that cannot be treated with traditional antibiotics has prompted the search for alternatives to combat bacterial infections. Endolysins, which are bacteriophage-derived peptidoglycan hydrolases, are attractive tools in this fight. Several studies have already demonstrated the efficacy of endolysins in targeting bacterial infections. Endolysins encoded by bacteriophages that infect Gram-positive bacteria typically possess an N-terminal catalytic domain and a C-terminal cell-wall binding domain (CWBD). In this study, we have uncovered the molecular mechanisms that underlie formation of a homodimer of Cpl-1, an endolysin that targets Streptococcus pneumoniae. Here, we use site-directed mutagenesis, analytical size exclusion chromatography, and analytical ultracentrifugation to disprove a previous suggestion that three residues at the N-terminus of the CWBD are involved in the formation of a Cpl-1 dimer in the presence of choline in solution. We conclusively show that the C-terminal tail region of Cpl-1 is involved in formation of the dimer. Alanine scanning mutagenesis generated various tail mutant constructs that allowed identification of key residues that mediate Cpl-1 dimer formation. Finally, our results allowed identification of a consensus sequence (FxxEPDGLIT) required for choline-dependent dimer formation─a sequence that occurs frequently in pneumococcal autolysins and endolysins. These findings shed light on the mechanisms of Cpl-1 and related enzymes and can be used to inform future engineering efforts for their therapeutic development against S. pneumoniae.

Bibliographic Details

Alreja, Adit B; Linden, Sara B; Lee, Harrison R; Chao, Kinlin L; Herzberg, Osnat; Nelson, Daniel C

American Chemical Society (ACS)

Medicine

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