5GS8

Crystal structure of TLA-3 extended-spectrum beta-lactamase

5GS8 の概要

• エントリーDOI: 10.2210/pdb5gs8/pdb
• 分子名称: Beta-lactamase, SULFATE ION, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: extended-spectrum beta-lactamase, hydrolase
• 由来する生物種: Serratia marcescens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32242.84

構造登録者

Wachino, J.,Jin, W.,Arakawa, Y. (登録日: 2016-08-14, 公開日: 2017-07-12, 最終更新日: 2023-11-08)

主引用文献

Jin, W.,Wachino, J.,Yamaguchi, Y.,Kimura, K.,Kumar, A.,Yamada, M.,Morinaka, A.,Sakamaki, Y.,Yonezawa, M.,Kurosaki, H.,Arakawa, Y.
Structural Insights into the TLA-3 Extended-Spectrum beta-Lactamase and Its Inhibition by Avibactam and OP0595.
Antimicrob. Agents Chemother., 61:-, 2017

PubMed Abstract: The development of effective inhibitors that block extended-spectrum β-lactamases (ESBLs) and restore the action of β-lactams represents an effective strategy against ESBL-producing We evaluated the inhibitory effects of the diazabicyclooctanes avibactam and OP0595 against TLA-3, an ESBL that we identified previously. Avibactam and OP0595 inhibited TLA-3 with apparent inhibitor constants () of 1.71 ± 0.10 and 1.49 ± 0.05 μM, respectively, and could restore susceptibility to cephalosporins in the TLA-3-producing strain. The value of the second-order acylation rate constant (/, where is the acylation rate constant and is the equilibrium constant) of avibactam [(3.25 ± 0.03) × 10 M · s] was closer to that of class C and D β-lactamases (/, <10 M · s) than that of class A β-lactamases (/, >10 M · s). In addition, we determined the structure of TLA-3 and that of TLA-3 complexed with avibactam or OP0595 at resolutions of 1.6, 1.6, and 2.0 Å, respectively. TLA-3 contains an inverted Ω loop and an extended loop between the β5 and β6 strands (insertion after Ser237), which appear only in PER-type class A β-lactamases. These structures might favor the accommodation of cephalosporins harboring bulky R1 side chains. TLA-3 presented a high catalytic efficiency (/ ) against cephalosporins, including cephalothin, cefuroxime, and cefotaxime. Avibactam and OP0595 bound covalently to TLA-3 via the Ser70 residue and made contacts with residues Ser130, Thr235, and Ser237, which are conserved in ESBLs. Additionally, the sulfate group of the inhibitors formed polar contacts with amino acid residues in a positively charged pocket of TLA-3. Our findings provide a structural template for designing improved diazabicyclooctane-based inhibitors that are effective against ESBL-producing .

PubMed: 28739781
DOI: 10.1128/AAC.00501-17

実験手法

X-RAY DIFFRACTION (1.59 Å)