1GQR

ACETYLCHOLINESTERASE (E.C. 3.1.1.7) COMPLEXED WITH RIVASTIGMINE

Summary for 1GQR

• Entry DOI: 10.2210/pdb1gqr/pdb
• Related: 1ACJ 1ACL 1AMN 1AX9 1CFJ 1DX6 1E3Q 1E66 1EA5 1EEA 1EVE 1FSS 1GPK 1GPN 1GQS 1HBJ 1OCE 1QID 1QIE 1QIF 1QIG 1QIH 1QII 1QIJ 1QIK 1QIM 1QTI 1SOM 1VOT 1VXO 1VXR 2ACE 2ACK 2DFP 3ACE 4ACE
• Descriptor: ACETYLCHOLINESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose, 3-[(1S)-1-(DIMETHYLAMINO)ETHYL]PHENOL, ... (5 entities in total)
• Functional Keywords: hydrolase, neurotransmitter cleavage
• Biological source: TORPEDO CALIFORNICA (PACIFIC ELECTRIC RAY)
• Cellular location: Isoform H: Cell membrane; Lipid-anchor, GPI- anchor. Isoform T: Cell membrane; Peripheral membrane protein: P04058
• Total number of polymer chains: 1
• Total formula weight: 60902.73

Authors

Raves, M.L.,Harel, M.,Silman, I.,Sussman, J.L. (deposition date: 2001-12-04, release date: 2002-03-15, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)