Allosteric modulation of acetylcholinesterase activity by peripheral ligands involves a conformational transition of the anionic subsite

The dynamic behavior of the cysteine loop plays an important role in the conformational state of Trp at position 86, which regulates the mechanism of allosteric effect in acetylcholinesterase (AChE). Substitutions of residues Asp74, Trp286 and Tyr72, parts of the peripheral anionic site (PAS) of human AChE, affect the binding and inhibition by propidium. Mutations in the residues Trp86 and Tyr133 have no influence on binding though they affect inhibition indicating that the allosteric mechanism of inhibition mediated by PAS involves changes in these residues.