Bibliographic Details
| Title: |
An active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M β-lactamase drug-resistance enzymes. |
| Authors: |
Lu, Shuo, Hu, Liya, Lin, Hanfeng, Judge, Allison, Rivera, Paola, Palaniappan, Murugesan, Sankaran, Banumathi, Wang, Jin, Prasad, B. V. Venkataram, Palzkill, Timothy |
| Source: |
Nature Communications; 11/8/2022, Vol. 13 Issue 1, p1-13, 13p |
| Subject Terms: |
BETA-lactamase inhibitors, BETA lactam antibiotics, ANTIBIOTICS, BINDING sites, HYDROLYSIS, DRUG resistance in bacteria, ENZYMES |
| Abstract: |
β-lactamases inactivate β-lactam antibiotics leading to drug resistance. Consequently, inhibitors of β-lactamases can combat this resistance, and the β-lactamase inhibitory protein (BLIP) is a naturally occurring inhibitor. The widespread CTX-M-14 and CTX-M-15 β-lactamases have an 83% sequence identity. In this study, we show that BLIP weakly inhibits CTX-M-14 but potently inhibits CTX-M-15. The structure of the BLIP/CTX-M-15 complex reveals that binding is associated with a conformational change of an active site loop of β-lactamase. Surprisingly, the loop structure in the complex is similar to that in a drug-resistant variant (N106S) of CTX-M-14. We hypothesized that the pre-established favorable loop conformation of the N106S mutant would facilitate binding. The N106S substitution results in a ~100- and 10-fold increase in BLIP inhibition potency for CTX-M-14 and CTX-M-15, respectively. Thus, this indicates that an active site loop in β-lactamase toggles between conformations that control antibiotic hydrolysis and inhibitor susceptibility. These findings highlight the role of accessible active site conformations in controlling enzyme activity and inhibitor susceptibility as well as the influence of mutations in selectively stabilizing discrete conformations. β-lactamases are a source of antibiotic resistance. Here, the authors show that an active site loop in β-lactamase toggles between conformations that control antibiotic hydrolysis and inhibitor susceptibility, highlighting the role of active site conformations in enzyme activity and inhibition. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
