1E66

STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH (-)-HUPRINE X AT 2.1A RESOLUTION

Summary for 1E66

• Entry DOI: 10.2210/pdb1e66/pdb
• Related: 1ACJ 1ACL 1AMN 1AX9 1CFJ 1DX6 1E3Q 1EEA 1EVE 1FSS 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-CHLORO-9-ETHYL-6,7,8,9,10,11-HEXAHYDRO-7,11-METHANOCYCLOOCTA[B]QUINOLIN-12-AMINE, ... (4 entities in total)
• Functional Keywords: cholinesterase, huprine x, alzheimer's disease, chemical hybrid, hydrolase
• Biological source: TORPEDO CALIFORNICA (PACIFIC ELECTRIC RAY)
• Total number of polymer chains: 1
• Total formula weight: 62066.32

Authors

Dvir, H.,Harel, M.,Silman, I.,Sussman, J.L. (deposition date: 2000-08-08, release date: 2001-08-02, Last modification date: 2024-10-23)

Primary citation

Dvir, H.,Wong, D.M.,Harel, M.,Barril, X.,Orozco, M.,Luque, F.J.,Munoz-Torrero, D.,Camps, P.,Rosenberry, T.L.,Silman, I.,Sussman, J.L.
3D Structure of Torpedo Californica Acetylcholinesterase Complexed with Huprine X at 2. 1 A Resolution: Kinetic and Molecular Dynamic Correlates.
Biochemistry, 41:2970-, 2002

PubMed Abstract: Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117.

PubMed: 11863435
DOI: 10.1021/BI011652I

Experimental method

X-RAY DIFFRACTION (2.1 Å)