title: The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design.
abstract: Bifunctional derivatives of the alkaloid galanthamine, designed to interact with both the active site of the enzyme acetylcholinesterase (AChE) and its peripheral cation binding site, have been assayed with Torpedo californica AChE (TcAChE), and the three-dimensional structures of their complexes with the enzyme have been solved by X-ray crystallography. Differences were noted between the IC(50) values obtained for TcAChE and those for Electrophorus electricus AChE. These differences are ascribed to sequence differences in one or two residues lining the active-site gorge of the enzyme. The binding of one of the inhibitors disrupts the native conformation of one wall of the gorge, formed by the loop Trp279-Phe290. It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine, which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen in the crystal structure.
authors.affiliation: Departments of Structural Biology and Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Harry M
authors.initials: HM
authors.lastname: Greenblatt
authors.forename: Catherine
authors.initials: C
authors.lastname: Guillou
authors.forename: Daniel
authors.initials: D
authors.lastname: Guénard
authors.forename: Anat
authors.initials: A
authors.lastname: Argaman
authors.forename: Simone
authors.initials: S
authors.lastname: Botti
authors.forename: Bernard
authors.initials: B
authors.lastname: Badet
authors.forename: Claude
authors.initials: C
authors.lastname: Thal
authors.forename: Israel
authors.initials: I
authors.lastname: Silman
authors.forename: Joel L
authors.initials: JL
authors.lastname: Sussman
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004593:Electrophorus / Q000378:metabolism; D005702:Galantamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014101:Torpedo / Q000378:metabolism*
chemical_list: D002800:Cholinesterase Inhibitors; D005702:Galantamine; D000110:Acetylcholinesterase