3FYZ

OXA-24 beta-lactamase complex with SA4-17 inhibitor

3FYZ の概要

• エントリーDOI: 10.2210/pdb3fyz/pdb
• 関連するPDBエントリー: 3FV7 3FZC
• 分子名称: Beta-lactamase OXA-24, (2S,3R)-2-[(7-aminocarbonyl-2-methanoyl-indolizin-3-yl)amino]-4-aminocarbonyloxy-3-methyl-3-sulfino-butanoic acid, TETRAETHYLENE GLYCOL, ... (4 entities in total)
• 機能のキーワード: b-lactamases, enzyme mechanism, carbapenem, inhibitors, hydrolase
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28207.29

構造登録者

Romero, A.,Santillana, E. (登録日: 2009-01-23, 公開日: 2010-02-09, 最終更新日: 2023-11-22)

主引用文献

Bou, G.,Santillana, E.,Sheri, A.,Beceiro, A.,Sampson, J.M.,Kalp, M.,Bethel, C.R.,Distler, A.M.,Drawz, S.M.,Pagadala, S.R.,van den Akker, F.,Bonomo, R.A.,Romero, A.,Buynak, J.D.
Design, synthesis, and crystal structures of 6-alkylidene-2'-substituted penicillanic acid sulfones as potent inhibitors of Acinetobacter baumannii OXA-24 carbapenemase.
J.Am.Chem.Soc., 132:13320-13331, 2010

PubMed Abstract: Class D β-lactamases represent a growing and diverse class of penicillin-inactivating enzymes that are usually resistant to commercial β-lactamase inhibitors. As many such enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel β-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2'-substituted penicillanic acid sulfones (1-5) were synthesized and tested against OXA-24, a clinically important β-lactamase that inactivates carbapenems and is found in A. baumannii. Based upon the roles Tyr112 and Met223 play in the OXA-24 β-lactamase, we also engineered two variants (Tyr112Ala and Tyr112Ala,Met223Ala) to test the hypothesis that the hydrophobic tunnel formed by these residues influences inhibitor recognition. IC(50) values against OXA-24 and two OXA-24 β-lactamase variants ranged from 10 ± 1 (4 vs WT) to 338 ± 20 nM (5 vs Tyr112Ala, Met223Ala). Compound 4 possessed the lowest K(i) (500 ± 80 nM vs WT), and 1 possessed the highest inactivation efficiency (k(inact)/K(i) = 0.21 ± 0.02 μM(-1)  s(-1)). Electrospray ionization mass spectrometry revealed a single covalent adduct, suggesting the formation of an acyl-enzyme intermediate. X-ray structures of OXA-24 complexed to four inhibitors (2.0-2.6 Å) reveal the formation of stable bicyclic aromatic intermediates with their carbonyl oxygen in the oxyanion hole. These data provide the first structural evidence that 6-alkylidene-2'-substituted penicillin sulfones are effective mechanism-based inactivators of class D β-lactamases. Their unique chemistry makes them developmental candidates. Mechanisms for class D hydrolysis and inhibition are discussed, and a pathway for the evolution of the BlaR1 sensor of Staphylococcus aureus to the class D β-lactamases is proposed.

PubMed: 20822105
DOI: 10.1021/ja104092z

実験手法

X-RAY DIFFRACTION (2.1 Å)