STRUCTURAL BASES FOR THE SPECIFICITY OF CHOLINESTERASE CATALYSIS AND INHIBITION

The availability of a crystal structure and comparative sequences of t he cholinesterases has provided templates suitable for analyzing the m olecular 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 spe cificity of carboxylesters, the stereospecificity of enantiomeric alky lphosphonates and the selectivity of tricyclic aromatic compounds in t he 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.