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Updated: Feb 8, 2026
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Analysis of Yersinia enterocolitica Effector Translocation into Host Cells Using Beta-lactamase Effector Fusions
Published on: October 13, 2015
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Targeting a hidden site on class A beta-lactamases
Fatma Gizem Avci1, Fatma Ece Altinisik1, Ipek Karacan1
1Marmara University, Department of Bioengineering, Istanbul, Turkey.
Journal of Molecular Graphics & Modelling
|July 1, 2018
Summary
Researchers explored a hidden pocket in TEM-1 beta-lactamase to find new antimicrobial drug candidates. They identified a compound that competitively inhibits the enzyme, demonstrating a promising new strategy for combating antibiotic resistance.
Area of Science:
- Biochemistry
- Drug Discovery
- Structural Biology
Background:
- Antibiotic resistance necessitates novel inhibitors for beta-lactamase enzymes.
- Allosteric inhibitors offer an alternative to traditional orthosteric inhibitors.
- TEM-1 beta-lactamase is a key target for antimicrobial development.
Purpose of the Study:
- To investigate the structural basis of inhibition in a hidden allosteric site of TEM-1 beta-lactamase.
- To characterize the kinetic mechanism and specificity of a novel allosteric inhibitor, CYMAL-6.
- To identify new chemical scaffolds targeting this allosteric site through virtual screening.
Main Methods:
- Crystallographic analysis to identify the binding site.
- Enzyme activity assays to determine inhibition kinetics and specificity.
- Virtual screening of a large compound library using molecular docking simulations.
Main Results:
- CYMAL-6 competitively inhibits wild-type TEM-1 beta-lactamase with an IC50 of 100 μM, showing specificity and non-aggregation-based inhibition.
- Virtual screening identified top-scoring compounds that interact with the allosteric pocket via hydrophobic and pi-cation interactions.
- The identified compounds target a pocket between H10 and H11 helices, engaging Arg244.
Conclusions:
- A hidden, druggable allosteric site in TEM-1 beta-lactamase has been characterized.
- CYMAL-6 serves as a lead compound for allosteric inhibition.
- Novel chemical scaffolds targeting this site offer a new strategy for developing antimicrobials against resistant bacteria.
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