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J. Biol. Chem., Vol. 277, Issue 45, 43301-43308, November 8, 2002

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Inhibitors of Different Structure Induce Distinguishing Conformations in the Omega Loop, Cys⁶⁹-Cys⁹⁶, of Mouse Acetylcholinesterase^*

Jianxin Shi, Zoran Radi, and Palmer Taylor

From the Department of Pharmacology, University of California, San Diego, La Jolla, California 92093

We have shown previously that association of reversible active site ligands induces a conformational change in an omega loop ( loop), Cys⁶⁹-Cys⁹⁶, of acetylcholinesterase. The fluorophore acrylodan, site-specifically incorporated at positions 76, 81, and 84, on the external portion of the loop not lining the active site gorge, shows changes in its fluorescence spectrum that reflect the fluorescent side chain moving from a hydrophobic environment to become more solvent-exposed. This appears to result from a movement of the  loop accompanying ligand binding. We show here that the loop is indeed flexible and responds to conformational changes induced by both active center and peripheral site inhibitors (gallamine and fasciculin). Moreover, phosphorylation and carbamoylation of the active center serine shows distinctive changes in acrylodan fluorescence spectra at the  loop sites, depending on the chirality and steric dimensions of the covalently conjugated ligand. Capping of the gorge with fasciculin, although it does not displace the bound ligand, dominates in inducing a conformational change in the loop. Hence, the ligand-induced conformational changes are distinctive and suggest multiple loop conformations accompany conjugation at the active center serine. The fluorescence changes induced by the modified enzyme may prove useful in the detection of organophosphates or exposure to cholinesterase inhibitors.

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