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J. Biol. Chem., Vol. 278, Issue 42, 41141-41147, October 17, 2003

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Crystal Structure of Human Butyrylcholinesterase and of Its Complexes with Substrate and Products^*

Yvain Nicolet  , Oksana Lockridge ¶, Patrick Masson ||, Juan C. Fontecilla-Camps  ** and Florian Nachon ¶ ||

From the Laboratoire de Cristallographie et Cristallogénèse des Protéines, Institut de Biologie Structurale "Jean-Pierre Ebel," CEA, UJF, CNRS, 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France, the ^¶University of Nebraska Medical Center, Eppley Research Institute, Omaha, NE 68198-6805, and the ^||Centre de Recherches du Service de Santé des Armées, Unité d'Enzymologie, 24 Avenue des Maquis du Grésivaudan, BP 87-38702 La Tronche CEDEX, France

Cholinesterases are among the most efficient enzymes known. They are divided into two groups: acetylcholinesterase, involved in the hydrolysis of the neurotransmitter acetylcholine, and butyrylcholinesterase of unknown function. Several crystal structures of the former have shown that the active site is located at the bottom of a deep and narrow gorge, raising the question of how substrate and products enter and leave. Human butyrylcholinesterase (BChE) has attracted attention because it can hydrolyze toxic esters such as cocaine or scavenge organophosphorus pesticides and nerve agents. Here we report the crystal structures of several recombinant truncated human BChE complexes and conjugates and provide a description for mechanistically relevant non-productive substrate and product binding. As expected, the structure of BChE is similar to a previously published theoretical model of this enzyme and to the structure of Torpedo acetylcholinesterase. The main difference between the experimentally determined BChE structure and its model is found at the acyl binding pocket that is significantly bigger than expected. An electron density peak close to the catalytic Ser¹⁹⁸ has been modeled as bound butyrate.

Received for publication, October 7, 2002 , and in revised form, July 2, 2003.

The atomic coordinates and structure factors (code P0I, 1P0Q, 1P0M, and 1P0P) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Chemistry, Massachusetts Inst. of Technology, Cambridge, MA 02139.

^** To whom correspondence should be addressed. Tel.: 33-438785920; Fax: 33-438785122; E-mail: juan{at}lccp.ibs.fr.

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