6D3G

PER-2 class A extended-spectrum beta-lactamase crystal structure in complex with avibactam at 2.4 Angstrom resolution

Summary for 6D3G

• Entry DOI: 10.2210/pdb6d3g/pdb
• Descriptor: Beta-lactamase, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, TETRAETHYLENE GLYCOL, ... (4 entities in total)
• Functional Keywords: dbo, penicilloil-serine-transferase, antibiotic resistance, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Citrobacter freundii
• Total number of polymer chains: 4
• Total formula weight: 125088.58

Authors

Power, P.,Ruggiero, M.,Gutkind, G.,Bonomo, R.,Klinke, S. (deposition date: 2018-04-16, release date: 2019-04-24, Last modification date: 2024-11-06)

Primary citation

Ruggiero, M.,Papp-Wallace, K.M.,Brunetti, F.,Barnes, M.D.,Bonomo, R.A.,Gutkind, G.,Klinke, S.,Power, P.
Structural Insights into the Inhibition of the Extended-Spectrum beta-Lactamase PER-2 by Avibactam.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: The diazabicyclooctane (DBO) avibactam (AVI) reversibly inactivates most serine-β-lactamases. Previous investigations showed that inhibition constants of AVI toward class A PER-2 are reminiscent of values observed for class C and D β-lactamases (i.e., / of ≈10 M s) but lower than other class A β-lactamases (i.e., / = 10 to 10 M s). Herein, biochemical and structural studies were conducted with PER-2 and AVI to explore these differences. Furthermore, biochemical studies on Arg220 and Thr237 variants with AVI were conducted to gain deeper insight into the mechanism of PER-2 inactivation. The main biochemical and structural observations revealed the following: (i) both amino-acid substitutions in Arg220 and the rich hydrophobic content in the active site hinder the binding of catalytic waters and acylation, impairing AVI inhibition; (ii) movement of Ser130 upon binding of AVI favors the formation of a hydrogen bond with the sulfate group of AVI; and (iii) the Thr237Ala substitution alters the AVI inhibition constants. The acylation constant (/) of PER-2 by AVI is primarily influenced by stabilizing hydrogen bonds involving AVI and important residues such as Thr237 and Arg220. (Variants in Arg220 demonstrate a dramatic reduction in /) We also observed that displacement of Ser130 side chain impairs AVI acylation, an observation not made in other extended-spectrum β-lactamases (ESBLs). Comparatively, relebactam combined with a β-lactam is more potent against producing PER-2 variants than β-lactam-AVI combinations. Our findings provide a rationale for evaluating the utility of the currently available DBO inhibitors against unique ESBLs like PER-2 and anticipate the effectiveness of these inhibitors toward variants that may eventually be selected upon AVI usage.

PubMed: 31235626
DOI: 10.1128/AAC.00487-19

Experimental method

X-RAY DIFFRACTION (2.398 Å)