1GQS

ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH NAP

1GQS の概要

• エントリーDOI: 10.2210/pdb1gqs/pdb
• 関連するPDBエントリー: 1ACJ 1ACL 1AMN 1AX9 1CFJ 1DX6 1E3Q 1E66 1EA5 1EEA 1EVE 1FSS 1GPK 1GPN 1GQR 1HBJ 1OCE 1QID 1QIE 1QIF 1QIG 1QIH 1QII 1QIJ 1QIK 1QIM 1QTI 1SOM 1VOT 1VXO 1VXR 2ACE 2ACK 2DFP 3ACE 4ACE
• 分子名称: ACETYLCHOLINESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose, 3-[(1S)-1-(DIMETHYLAMINO)ETHYL]PHENOL, ... (4 entities in total)
• 機能のキーワード: hydrolase, neurotransmitter cleavage, anti-alzheimer drug
• 由来する生物種: TORPEDO CALIFORNICA (PACIFIC ELECTRIC RAY)
• 細胞内の位置: Isoform H: Cell membrane; Lipid-anchor, GPI- anchor. Isoform T: Cell membrane; Peripheral membrane protein: P04058
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 60801.63

構造登録者

Bar-on, P.,Millard, C.B.,Harel, M.,Dvir, H.,Enz, A.,Sussman, J.L.,Silman, I. (登録日: 2001-12-04, 公開日: 2002-03-15, 最終更新日: 2024-10-16)

主引用文献

Bar-on, P.,Millard, C.B.,Harel, M.,Dvir, H.,Enz, A.,Sussman, J.L.,Silman, I.
Kinetic and Structural Studies on the Interaction of Cholinesterases with the Anti-Alzheimer Drug Rivastigmine
Biochemistry, 41:3555-, 2002

PubMed Abstract: Rivastigmine, a carbamate inhibitor of acetylcholinesterase, is already in use for treatment of Alzheimer's disease under the trade name of Exelon. Rivastigmine carbamylates Torpedo californica acetylcholinesterase very slowly (k(i) = 2.0 M(-1) min(-1)), whereas the bimolecular rate constant for inhibition of human acetylcholinesterase is >1600-fold higher (k(i) = 3300 M(-1) min(-1)). For human butyrylcholinesterase and for Drosophila melanogaster acetylcholinesterase, carbamylation is even more rapid (k(i) = 9 x 10(4) and 5 x 10(5) M(-1) min(-1), respectively). Spontaneous reactivation of all four conjugates is very slow, with <10% reactivation being observed for the Torpedo enzyme after 48 h. The crystal structure of the conjugate of rivastigmine with Torpedo acetylcholinesterase was determined to 2.2 A resolution. It revealed that the carbamyl moiety is covalently linked to the active-site serine, with the leaving group, (-)-S-3-[1-(dimethylamino)ethyl]phenol, being retained in the "anionic" site. A significant movement of the active-site histidine (H440) away from its normal hydrogen-bonded partner, E327, was observed, resulting in disruption of the catalytic triad. This movement may provide an explanation for the unusually slow kinetics of reactivation.

PubMed: 11888271
DOI: 10.1021/BI020016X

実験手法

X-RAY DIFFRACTION (3 Å)