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J Biol Chem, Vol. 274, Issue 39, 27740-27746, September 24, 1999

The Binding Sites of Inhibitory Monoclonal Antibodies on Acetylcholinesterase
IDENTIFICATION OF A NOVEL REGULATORY SITE AT THE PUTATIVE "BACK DOOR"

Stéphanie Simon, Anne Le Goff, Yveline Frobert^¶, Jacques Grassi^¶, and Jean Massoulié

From the  Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS URA 1857, Ecole Normale Supérieure, 46 rue d'Ulm, 75005 Paris, France and the ^¶ Service de Pharmacologie et d'Immunologie, CEA-Saclay, 91191 Gif sur Yvette cedex, France

We investigated the target sites of three inhibitory monoclonal antibodies on Electrophorus acetylcholinesterase (AChE). Previous studies showed that Elec-403 and Elec-410 are directed to overlapping but distinct epitopes in the peripheral site, at the entrance of the catalytic gorge, whereas Elec-408 binds to a different region. Using Electrophorus/rat AChE chimeras, we identified surface residues that differed between sensitive and insensitive AChEs: the replacement of a single Electrophorus residue by its rat homolog was able to abolish binding and inhibition, for each antibody. Reciprocally, binding and inhibition by Elec-403 and by Elec-410 could be conferred to rat AChE by the reverse mutation. Elec-410 appears to bind to one side of the active gorge, whereas Elec-403 covers its opening, explaining why the AChE-Elec-410 complex reacts faster than the AChE-Elec-403 or AChE-fasciculin complexes with two active site inhibitors, m-(N,N,N-trimethyltammonio)trifluoro-acetophenone and echothiophate. Elec-408 binds to the region of the putative "back door," distant from the peripheral site, and does not interfere with the access of inhibitors to the active site. The binding of an antibody to this novel regulatory site may inhibit the enzyme by blocking the back door or by inducing a conformational distortion within the active site.

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