8DE0

TEM-1 beta-lactamase covalently bound to avibactam

8DE0 の概要

• エントリーDOI: 10.2210/pdb8de0/pdb
• 分子名称: Beta-lactamase TEM, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide (3 entities in total)
• 機能のキーワード: hydrolase, beta-lactamase, tem, avibactam, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 116944.86

構造登録者

Ji, Z.,Boxer, S.G.,Mathews, I.I. (登録日: 2022-06-19, 公開日: 2022-09-07, 最終更新日: 2024-11-13)

主引用文献

Ji, Z.,Kozuch, J.,Mathews, I.I.,Diercks, C.S.,Shamsudin, Y.,Schulz, M.A.,Boxer, S.G.
Protein Electric Fields Enable Faster and Longer-Lasting Covalent Inhibition of beta-Lactamases.
J.Am.Chem.Soc., 144:20947-20954, 2022

PubMed Abstract: The widespread design of covalent drugs has focused on crafting reactive groups of proper electrophilicity and positioning toward targeted amino-acid nucleophiles. We found that environmental electric fields projected onto a reactive chemical bond, an overlooked design element, play essential roles in the covalent inhibition of TEM-1 β-lactamase by avibactam. Using the vibrational Stark effect, the magnitudes of the electric fields that are exerted by TEM active sites onto avibactam's reactive C═O were measured and demonstrate an electrostatic gating effect that promotes bond formation yet relatively suppresses the reverse dissociation. These results suggest new principles of covalent drug design and off-target site prediction. Unlike shape and electrostatic complementary which address binding constants, electrostatic catalysis drives reaction rates, essential for covalent inhibition, and deepens our understanding of chemical reactivity, selectivity, and stability in complex systems.

PubMed: 36324090
DOI: 10.1021/jacs.2c09876

実験手法

X-RAY DIFFRACTION (1.72 Å)