6SFE

CRYSTAL STRUCTURE OF DHQ1 FROM SALMONELLA TYPHI COVALENTLY MODIFIED BY COMPOUND 7

6SFE の概要

• エントリーDOI: 10.2210/pdb6sfe/pdb
• 分子名称: 3-dehydroquinate dehydratase, (1~{S},3~{S},4~{S},5~{R})-3-(aminomethyl)-3,4,5-tris(hydroxyl)cyclohexane-1-carboxylic acid (3 entities in total)
• 機能のキーワード: lyase activity, chorismate biosynthetic process, 3-dehydroquinase, covalent inhibitor, lyase
• 由来する生物種: Salmonella typhi
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55772.40

構造登録者

Sanz-Gaitero, M.,Lence, E.,Maneiro, M.,Thompson, R.,Hawkins, A.R.,Gonzalez-Bello, C.,van Raaij, M.J. (登録日: 2019-08-01, 公開日: 2020-04-15, 最終更新日: 2024-11-20)

主引用文献

Lence, E.,Maneiro, M.,Sanz-Gaitero, M.,van Raaij, M.J.,Thompson, P.,Hawkins, A.R.,Gonzalez-Bello, C.
Self-Immolation of a Bacterial Dehydratase Enzyme by its Epoxide Product.
Chemistry, 26:8035-8044, 2020

PubMed Abstract: Disabling the bacterial capacity to cause infection is an innovative approach that has attracted significant attention to fight against superbugs. A relevant target for anti-virulence drug discovery is the type I dehydroquinase (DHQ1) enzyme. It was shown that the 2-hydroxyethylammonium derivative 3 has in vitro activity since it causes the covalent modification of the catalytic lysine residue of DHQ1. As this compound does not bear reactive electrophilic centers, how the chemical modification occurs is intriguing. We report here an integrated approach, which involves biochemical studies, X-ray crystallography and computational studies on the reaction path using combined quantum mechanics/molecular mechanics Umbrella Sampling Molecular Dynamics, that evidences that DHQ1 catalyzes its self-immolation by transforming the unreactive 2-hydroxyethylammonium group in 3 into an epoxide that triggers the lysine covalent modification. This finding might open opportunities for the design of lysine-targeted irreversible inhibitors bearing a 2-hydroxyethylammonium moiety as an epoxide proform, which to our knowledge has not been reported previously.

PubMed: 32259333
DOI: 10.1002/chem.202000759

実験手法

X-RAY DIFFRACTION (1.08 Å)