期刊
MOLECULAR MICROBIOLOGY
卷 117, 期 6, 页码 1464-1478出版社
WILEY
DOI: 10.1111/mmi.14921
关键词
inhibitor design; quorum sensing; Rgg transcriptional regulators; Streptococcus pneumoniae; structure-function
资金
- National Institute of Allergy and Infectious Diseases [R01 AI135060--01A1, R01 AI139077--01A1]
The importance of each residue within the active short hydrophobic peptide (SHP) in the Streptococcus pneumoniae Rgg144/SHP144 regulator-peptide quorum sensing system was characterized by this study. The study identified key interactions and mechanisms of activation in this critical pneumococcal QS system, providing a theoretical basis for the development of inhibitors.
The Streptococcus pneumoniae Rgg144/SHP144 regulator-peptide quorum sensing (QS) system is critical for nutrient utilization, oxidative stress response, and virulence. Here, we characterized this system by assessing the importance of each residue within the active short hydrophobic peptide (SHP) by alanine-scanning mutagenesis and testing the resulting peptides for receptor binding and activation of the receptor. Interestingly, several of the mutations had little effect on binding to Rgg144 but reduced transcriptional activation appreciably. In particular, a proline substitution (P21A) reduced transcriptional activation by 29-fold but bound with a 3-fold higher affinity than the wild-type SHP. Consistent with the function of Rgg144, the mutant peptide led to decreased utilization of mannose and increased susceptibility to superoxide generator paraquat. Pangenome comparison showed full conservation of P21 across SHP144 allelic variants. Crystallization of Rgg144 in the absence of peptide revealed a comparable structure to the DNA bound and free forms of its homologs suggesting similar mechanisms of activation. Together, these analyses identify key interactions in a critical pneumococcal QS system. Further manipulation of the SHP has the potential to facilitate the development of inhibitors that are functional across strains. The approach described here is likely to be effective across QS systems in multiple species.
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