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Abstract
Declining efficiency of antibiotic-inhibitor combinatorial therapies in treating beta-lactamase mediated resistance necessitates novel inhibitor development. Allosteric inhibition offers an alternative to conventional drugs that target the conserved active site. Here, we show that the evolutionarily conserved PWP triad located at the N-terminus of the H10 helix directly interacts with the allosteric site in TEM-1 beta-lactamase and regulates its activity. While point mutations in the PWP triad preserve the overall secondary structures around the allosteric site, they result in a more open and dynamic global structure with decreased chemical stability and increased aggregation propensity. These mutant enzymes with a less compact hydrophobic core around the allosteric site displayed significant activity loss. Detailed sequence and structure conservation analyses revealed that the PWP triad is an evolutionarily conserved motif unique to class A beta-lactamases aligning its allosteric site and hence is an effective potential target for enzyme regulation and selective drug design.
Acknowledgements
We thank Dr. Olga Gursky for providing Circular Dichroism and Fluorescence Spectroscopy facilities and for many helpful discussions.
Declaration of interest
The authors report no declarations of interest. This work was supported by TUBITAK Research Grants 113M533 (BSA) and 109M229 (EO), 114M179 (EO), Marmara University Research Foundation FEN-C-YLP-181208-0290 (BSA) and Boğaziçi University Research Foundation 14A05D7 (EO).