ArticleBiochemistry2005
Structural consequences of the inhibitor-resistant Ser130Gly substitution in TEM beta-lactamase.
Article in Biochemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 70 citations in OpenAlex.
- Structural perspectives on clinical β-lactamase inhibitors: From mechanism to resistance.Journal of microbiology (Seoul, Korea) · 2026Review
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Positive epistasis drives clavulanic acid resistance in double mutant libraries of BlaC β-lactamase.Communications biology · 2024Article
- Mutation of the conserved Asp-Asp pair impairs the structure, function, and inhibition of CTX-M Class A β-lactamase.FEBS letters · 2021Article
- Assessment of Phenotype Relevant Amino Acid Residues in TEM-β-Lactamases by Mathematical Modelling and Experimental Approval.Microorganisms · 2021Article
- Variations in the SDN Loop of Class A Beta-Lactamases: A Study of the Molecular Mechanism of BlaC (Frontiers in microbiology · 2021Article
- A drug-resistant β-lactamase variant changes the conformation of its active-site proton shuttle to alter substrate specificity and inhibitor potency.The Journal of biological chemistry · 2020Article
- Unraveling the energetic significance of chemical events in enzyme catalysis via machine-learning based regression approach.Communications chemistry · 2020Article
- Structure-Based Analysis of Cryptic-Site Opening.Structure (London, England : 1993) · 2020Article
- Combination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination.Antimicrobial agents and chemotherapy · 2018Article
- Active-Site Protonation States in an Acyl-Enzyme Intermediate of a Class A β-Lactamase with a Monobactam Substrate.Antimicrobial agents and chemotherapy · 2017Article
- Characterization of the global stabilizing substitution A77V and its role in the evolution of CTX-M β-lactamases.Antimicrobial agents and chemotherapy · 2015Article
- Variants of β-lactamase KPC-2 that are resistant to inhibition by avibactam.Antimicrobial agents and chemotherapy · 2015Article
- Avibactam and inhibitor-resistant SHV β-lactamases.Antimicrobial agents and chemotherapy · 2015Article
- Combinatorial active-site variants confer sustained clavulanate resistance in BlaC β-lactamase from Mycobacterium tuberculosis.Protein science : a publication of the Protein Society · 2015Article
- Article
- Computer aided screening of potent inhibitor compounds against inhibitor resistant TEM β-lactamase mutants from traditional Chinese medicine.Bioinformation · 2014Article
- β-Lactamase inhibition by 7-alkylidenecephalosporin sulfones: allylic transposition and formation of an unprecedented stabilized acyl-enzyme.Journal of the American Chemical Society · 2013Article
- Can inhibitor-resistant substitutions in the Mycobacterium tuberculosis β-Lactamase BlaC lead to clavulanate resistance?: a biochemical rationale for the use of β-lactam-β-lactamase inhibitor combinations.Antimicrobial agents and chemotherapy · 2013Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Beta-lactamase confers resistance to penicillin-like antibiotics by hydrolyzing their beta-lactam bond. To combat these enzymes, inhibitors covalently cross-linking the hydrolytic Ser70 to Ser130 were introduced. In turn, mutant beta-lactamases have emerged with decreased susceptibility to these mechanism-based inhibitors. Substituting Ser130 with glycine in the inhibitor-resistant TEM (IRT) mutant TEM-76 (S130G) prevents the irreversible cross-linking step. Since the completely conserved Ser130 is thought to transfer a proton important for catalysis, its substitution might be hypothesized to result in a nonfunctional enzyme; this is clearly not the case. To investigate how TEM-76 remains active, its structure was determined by X-ray crystallography to 1.40 A resolution. A new water molecule (Wat1023) is observed in the active site, with two configurations located 1.1 and 1.3 A from the missing Ser130 Ogamma; this water molecule likely replaces the Ser130 side-chain hydroxyl in substrate hydrolysis. Intriguingly, this same water molecule is seen in the IRT TEM-32 (M69I/M182T), where Ser130 has moved significantly. TEM-76 shares other structural similarities with various IRTs; like TEM-30 (R244S) and TEM-84 (N276D), the water molecule activating clavulanate for cross-linking (Wat1614) is disordered (in TEM-30 it is actually absent). As expected, TEM-76 has decreased kinetic activity, likely due to the replacement of the Ser130 side-chain hydroxyl with a water molecule. In contrast to the recently determined structure of the S130G mutant in the related SHV-1 beta-lactamase, in TEM-76 the key hydrolytic water (Wat1561) is still present. The conservation of similar accommodations among IRT mutants suggests that resistance arises from common mechanisms, despite the disparate locations of the various substitutions.
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