1SIH

AGAO in covalent complex with the inhibitor MOBA ("4-(4-methylphenoxy)-2-butyn-1-amine")

1SIH の概要

• エントリーDOI: 10.2210/pdb1sih/pdb
• 関連するPDBエントリー: 1AV4 1SII
• 分子名称: Phenylethylamine oxidase, SULFATE ION, COPPER (II) ION, ... (6 entities in total)
• 機能のキーワード: cao, cuao, copper-containing, amine oxidase, tpq, quinone, trihydroxyphenylalanine quinone, moba, 4-(4-methylphenoxyoxy)-2-butyn-1-amine, 4-(aryloxy)-2-butynamine, suicide inhibition, oxidoreductase
• 由来する生物種: Arthrobacter globiformis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 72305.79

構造登録者

Guss, J.M.,Langley, D.B.,Duff, A.P. (登録日: 2004-02-29, 公開日: 2004-09-07, 最終更新日: 2024-10-30)

主引用文献

O'Connell, K.M.,Langley, D.B.,Shepard, E.M.,Duff, A.P.,Jeon, H.B.,Sun, G.,Freeman, H.C.,Guss, J.M.,Sayre, L.M.,Dooley, D.M.
Differential Inhibition of Six Copper Amine Oxidases by a Family of 4-(Aryloxy)-2-butynamines: Evidence for a New Mode of Inactivation.
Biochemistry, 43:10965-10978, 2004

PubMed Abstract: A series of compounds derived from a previously identified substrate analogue of copper amine oxidases (CuAOs) (Shepard et al. (2002) Eur. J. Biochem. 269, 3645-3658) has been screened against six different CuAOs with a view to designing potent and selective inhibitors. The substrate analogues investigated were 4-(1-naphthyloxy)-2-butyn-1-amine, 4-(2-methylphenoxy)-2-butyn-1-amine, 4-(3-methylphenoxy)-2-butyn-1-amine, 4-(4-methylphenoxy)-2-butyn-1-amine, and 4-phenoxy-2-butyn-1-amine. These compounds were screened against equine plasma amine oxidase (EPAO), Pisum sativum amine oxidase (PSAO), Pichia pastoris lysyl oxidase (PPLO), bovine plasma amine oxidase (BPAO), human kidney diamine oxidase (KDAO), and Arthrobacter globiformis amine oxidase (AGAO) to examine the effect of different substituent groups on potency. Despite the similar structures of the 4-aryloxy analogues evaluated, striking differences in potency were observed. In addition, crystal structures of AGAO derivitized with 4-(2-naphthyloxy)-2-butyn-1-amine and 4-(4-methylphenoxy)-2-butyn-1-amine were obtained at a resolution of 1.7 A. The structures reveal a novel and unprecedented reaction mechanism involving covalent attachment of the alpha,beta-unsaturated aldehyde turnover product to the amino group of the reduced 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor. Collectively, the structural and inhibition results support the feasibility of designing selective mechanism-based inhibitors of copper amine oxidases.

PubMed: 15323556
DOI: 10.1021/bi0492004

実験手法

X-RAY DIFFRACTION (1.73 Å)