3K9B

Crystal structure of human liver carboxylesterase 1 (hCE1) in covalent complex with the nerve agent Cyclosarin (GF)

3K9B の概要

• エントリーDOI: 10.2210/pdb3k9b/pdb
• 分子名称: Liver carboxylesterase 1, cyclohexyl (S)-methylphosphonofluoridoate (3 entities in total)
• 機能のキーワード: hydrolase, organophosphorus nerve agent, alternative splicing, disulfide bond, endoplasmic reticulum, glycoprotein, polymorphism, serine esterase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum lumen: P23141
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 175743.34

構造登録者

Hemmert, A.C.,Redinbo, M.R. (登録日: 2009-10-15, 公開日: 2010-01-19, 最終更新日: 2024-11-27)

主引用文献

Hemmert, A.C.,Otto, T.C.,Wierdl, M.,Edwards, C.C.,Fleming, C.D.,MacDonald, M.,Cashman, J.R.,Potter, P.M.,Cerasoli, D.M.,Redinbo, M.R.
Human carboxylesterase 1 stereoselectively binds the nerve agent cyclosarin and spontaneously hydrolyzes the nerve agent sarin.
Mol.Pharmacol., 77:508-516, 2010

PubMed Abstract: Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P(R) enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P(S) isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P(S) isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.

PubMed: 20051531
DOI: 10.1124/mol.109.062356

実験手法

X-RAY DIFFRACTION (3.1 Å)