Accession Number : ADP008867

Title :   3-D Structures of Acetylcholinesterase and of its Complexes with Cholinergic Ligands.

Corporate Author : WEIZMANN INST OF SCIENCE REHOVOT (ISRAEL)

Personal Author(s) : Sussman, Joel L. ; Harel, Michal ; Silman, Israel

Report Date : 13 MAY 1993

Pagination or Media Count : 10

Abstract : Our recent determination of the 3D-structure of AChE from Torpedo californica (1) reveals, for the first time at atomic resolution, a protein binding pocket for the neurotransmitter ACh. The active site contains a catalytic triad (S200-H440-E327) near the bottom of a deep and narrow gorge lined with the rings of 14 aromatic amino acid residues. We earlier suggested, on the basis of modelling which involved docking the ACh molecule in an all-trans conformation, that the quaternary group of the choline moiety makes close contact with the indole ring of W84. We have soaked into crystals of AChE a series of cholinergic ligands, and recently determined the 3-D structure of AChE:decamethonium, AChE:edrophonium and AChE:tacrine complexes. Decamethonium, a bisquaternary ligand, is both a depolarizing neuromuscular blocking drug and an anticholinesterase agent. Edrophonium is a drug used in treatment of myasthenia gravis, it contains a quaternary ammonium group and acts peripherally. Tacrine is a tertiary inhibitor which can penetrate the blood brain barrier, and is currently being evaluated for management of Alzheimer's disease. The crystal structures of these complexes are in good agreement with our modelling of the interaction of ACh with the active site of AChE, and clearly show the specific interactions of the drugs with AChE. These assignments should be invaluable in designing drugs and prophylactic agents targeted to the active site of AChE.

Descriptors :   *TORPEDOES, *ACETYLCHOLINESTERASE, *CHOLINESTERASE INHIBITORS, AGREEMENTS, ALLOCATIONS, AMINO ACIDS, BLOCKING, BLOOD BRAIN BARRIER, CANYONS, CHOLINES, CRYSTALS, DISEASES, DOCKING, DRUGS, INDOLES, INHIBITORS, INTERACTIONS, LIGANDS, MANAGEMENT, MOLECULES, NEUROTRANSMITTERS, PROTEINS, RESOLUTION, RINGS, SITES, STRUCTURES, TORPEDOES, HYDROLYSIS, X RAYS.

Subject Categories : Biochemistry
      Pharmacology

Distribution Statement : APPROVED FOR PUBLIC RELEASE