7S5S

CTX-M-15 WT in complex with BLIP WT

Summary for 7S5S

• Entry DOI: 10.2210/pdb7s5s/pdb
• Descriptor: Beta-lactamase, Beta-lactamase inhibitory protein (3 entities in total)
• Functional Keywords: beta-lactamase, antibiotic resistance, beta-lactamase inhibitory protein, protein complex, protein binding
• Biological source: Escherichia coli; More
• Total number of polymer chains: 2
• Total formula weight: 45567.19

Authors

Lu, S.,Palzkill, T.,Hu, L.Y.,Prasad, B.V.V.,Sankaran, B. (deposition date: 2021-09-11, release date: 2022-11-30, Last modification date: 2024-11-06)

Primary citation

Lu, S.,Hu, L.,Lin, H.,Judge, A.,Rivera, P.,Palaniappan, M.,Sankaran, B.,Wang, J.,Prasad, B.V.V.,Palzkill, T.
An active site loop toggles between conformations to control antibiotic hydrolysis and inhibition potency for CTX-M beta-lactamase drug-resistance enzymes.
Nat Commun, 13:6726-6726, 2022

PubMed 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.

PubMed: 36344533
DOI: 10.1038/s41467-022-34564-3

Experimental method

X-RAY DIFFRACTION (1.4 Å)