7EBA

Co-crystal of kurarinone with sEH

7EBA の概要

• エントリーDOI: 10.2210/pdb7eba/pdb
• 分子名称: Bifunctional epoxide hydrolase 2, (2S)-2-[2,4-bis(oxidanyl)phenyl]-5-methoxy-8-[(2R)-5-methyl-2-prop-1-en-2-yl-hex-4-enyl]-7-oxidanyl-2,3-dihydrochromen-4-one (3 entities in total)
• 機能のキーワード: seh, inhibitor, kurarinone, hydrolase, interaction, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77276.65

構造登録者

Sun, C.P.,Ma, X.C. (登録日: 2021-03-09, 公開日: 2022-03-09, 最終更新日: 2023-11-29)

主引用文献

Sun, C.P.,Zhou, J.J.,Yu, Z.L.,Huo, X.K.,Zhang, J.,Morisseau, C.,Hammock, B.D.,Ma, X.C.
Kurarinone alleviated Parkinson's disease via stabilization of epoxyeicosatrienoic acids in animal model.
Proc.Natl.Acad.Sci.USA, 119:e2118818119-e2118818119, 2022

PubMed Abstract: Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by loss of dopaminergic neurons in the substantia nigra (SN), causing bradykinesia and rest tremors. Although the molecular mechanism of PD is still not fully understood, neuroinflammation has a key role in the damage of dopaminergic neurons. Herein, we found that kurarinone, a unique natural product from , alleviated the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits and dopaminergic neurotoxicity, including the losses of neurotransmitters and tyrosine hydroxylase (TH)-positive cells (SN and striatum [STR]). Furthermore, kurarinone attenuated the MPTP-mediated neuroinflammation via suppressing the activation of microglia involved in the nuclear factor kappa B signaling pathway. The proteomics result of the solvent-induced protein precipitation and thermal proteome profiling suggest that the soluble epoxide hydrolase (sEH) enzyme, which is associated with the neuroinflammation of PD, is a promising target of kurarinone. This is supported by the increase of plasma epoxyeicosatrienoic acids (sEH substrates) and the decrease of dihydroxyeicosatrienoic acids (sEH products), and the results of in vitro inhibition kinetics, surface plasmon resonance, and cocrystallization of kurarinone with sEH revealed that this natural compound is an uncompetitive inhibitor. In addition, sEH knockout (KO) attenuated the progression of PD, and sEH KO plus kurarinone did not further reduce the protection of PD in MPTP-induced PD mice. These findings suggest that kurarinone could be a potential natural candidate for the treatment of PD, possibly through sEH inhibition.

PubMed: 35217618
DOI: 10.1073/pnas.2118818119

実験手法

X-RAY DIFFRACTION (2.3 Å)