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9qi3

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Crystal structure of I105Y/S130G double mutant of BlaC from Mycobacterium tuberculosis

Structural highlights

9qi3 is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BLAC_MYCBO Extended spectrum beta-lactamase (ESBL) that inactivates beta-lactam antibiotics by hydrolyzing the amide group of the beta-lactam ring. Displays high levels of penicillinase and cephalosporinase activity as well as measurable activity with carbapenems, including imipenem and meropenem. Plays a primary role in the intrinsic resistance of mycobacteria to beta-lactam antibiotics.[UniProtKB:P9WKD3]

Publication Abstract from PubMed

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 beta-lactamases, where synergistic mutations can enhance antimicrobial resistance. We recently demonstrated that positive epistasis drives clavulanic acid resistance in double-mutant libraries of the beta-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.

Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant beta-lactamase mutants.,Radojkovic M, Koene SF, Chikunova A, Florea BI, Natarajan SV, Boyle AL, Ubbink M Protein Sci. 2025 Nov;34(11):e70325. doi: 10.1002/pro.70325. PMID:41074856^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Radojković M, Koene SF, Chikunova A, Florea BI, Natarajan SV, Boyle AL, Ubbink M. Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants. Protein Sci. 2025 Nov;34(11):e70325. PMID:41074856 doi:10.1002/pro.70325