9QI3
Crystal structure of I105Y/S130G double mutant of BlaC from Mycobacterium tuberculosis
Summary for 9QI3
| Entry DOI | 10.2210/pdb9qi3/pdb |
| Descriptor | Beta-lactamase, ACETATE ION, ZINC ION, ... (5 entities in total) |
| Functional Keywords | beta-lactamase, blac, hydrolase |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 2 |
| Total formula weight | 56975.12 |
| Authors | |
| Primary citation | Radojkovic, M.,Koene, S.F.,Chikunova, A.,Florea, B.I.,Natarajan, S.V.,Boyle, A.L.,Ubbink, M. Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant beta-lactamase mutants. Protein Sci., 34:e70325-e70325, 2025 Cited by PubMed Abstract: Epistasis, the non-additive effect of mutations, substantially undermines our ability to predict the evolutionary trajectories of enzymes. Epistatic effects are evident in the evolution of serine β-lactamases, where synergistic mutations can enhance antimicrobial resistance. We recently demonstrated that positive epistasis drives clavulanic acid resistance in double-mutant libraries of the β-lactamase BlaC. Here, we employed various biochemical and structural approaches to investigate molecular mechanisms underlying epistasis in the fitness of two double mutant variants, I105Y-S130G and I105G-G132N. For the latter enzyme, epistatic compensation of catalytic activity was detected for multiple substrates and proved to be highly buffer-dependent. Non-additive effects were also evident in the thermostability profile of the I105G-G132N variant. The interplay between the reduced clavulanic acid sensitivity of the S130G and G132N variants and active-site modifications induced by Ile105 substitutions is discussed. The results demonstrate that the origins of epistasis can be rooted in multiple enzyme traits, highlighting its important role in the evolution of antimicrobial resistance. PubMed: 41074856DOI: 10.1002/pro.70325 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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