Structural bases for the specificity of cholinesterase catalysis and inhibition.
The availability of a crystal structure and comparative sequences of the cholinesterases has provided templates suitable for analyzing the molecular bases of specificity of reversible inhibitors, carbamoylating agents and organophosphates. Site-specific mutagenesis enables one to modify the structures of both the binding site and peptide ligand as well as create chimeras reflecting one type of esterase substituted in the template of another. Herein we define the bases for substrate specificity of carboxylesters, the stereospecificity of enantiomeric alkylphosphonates and the selectivity of tricyclic aromatic compounds in the active center of cholinesterase. We also describe the binding loci of the peripheral site and changes in catalytic parameters induced by peripheral site ligands, using the peptide fasciculin.
Taylor
P
P
Department of Pharmacology, University of California, San Diego, La Jolla 92093-0636, USA.
Radic
Z
Z
Hosea
N A
NA
Camp
S
S
Marchot
P
P
Berman
H A
HA
D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000737:chemistry* / Q000378:metabolism; D004546:Elapid Venoms / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D013379:Substrate Specificity
D002800:Cholinesterase Inhibitors; D004546:Elapid Venoms; C044937:fasciculin; D002802:Cholinesterases