Bartolucci_2001_Proteins_42_182

Reference

Title : Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs - Bartolucci_2001_Proteins_42_182
Author(s) : Bartolucci C , Perola E , Pilger C , Fels G , Lamba D
Ref : Proteins , 42 :182 , 2001
Abstract : The 3D structure of a complex of the anti-Alzheimer drug galanthamine with Torpedo californica acetylcholinesterase is reported. Galanthamine, a tertiary alkaloid extracted from several species of Amarylidacae, is so far the only drug that shows a dual activity, being both an acetylcholinesterase inhibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists. The X-ray structure, at 2.5A resolution, shows an unexpected orientation of the ligand within the active site, as well as unusual protein-ligand interactions. The inhibitor binds at the base of the active site gorge, interacting with both the acyl-binding pocket and the principal quaternary ammonium-binding site. However, the tertiary amine group of galanthamine does not directly interact with Trp84. A docking study using the program AUTODOCK correctly predicts the orientation of galanthamine in the active site. The docked lowest-energy structure has a root mean square deviation of 0.5A with respect to the corresponding crystal structure of the complex. The observed binding mode explains the affinities of a series of structural analogs of galanthamine and provides a rational basis for structure-based drug design of synthetic derivatives with improved pharmacological properties. Proteins 2001;42:182-191.
ESTHER : Bartolucci_2001_Proteins_42_182
PubMedSearch : Bartolucci_2001_Proteins_42_182
PubMedID: 11119642
Gene_locus related to this paper: torca-ACHE

Related information

Gene_locus related to this paper: torca-ACHE

Citations formats

Bartolucci C, Perola E, Pilger C, Fels G, Lamba D (2001)
Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs
Proteins 42 :182

Bartolucci C, Perola E, Pilger C, Fels G, Lamba D (2001)
Proteins 42 :182