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| Subject Categories: Structural Biology |
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| The EMBO Journal
(2006) 25, 2746–2756, doi:10.1038/sj.emboj.7601175 Published online 8 June 2006 |
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| Structural insights into substrate traffic and inhibition in acetylcholinesterase |
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| Jacques-Philippe Colletier1, Didier Fournier2, Harry M Greenblatt3, Jure Stojan4, Joel L Sussman3, Giuseppe Zaccai1, 6, Israel Silman5 and Martin Weik1 |
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1 Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale (CEA/CNRS/UJF), Grenoble Cedex, France 2 Groupe de Biotechnologie des Protéines, Institut de Pharmacologie et de Biologie Structurale (CNRS/UPS), Toulouse, France 3 Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel 4 Medical Faculty, Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia 5 Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel 6 Institut Laue-Langevin, Grenoble Cedex, France To whom correspondence should be addressed Martin Weik, Laboratoire de Biophysique Moléculaire, Institut de Biologie Structurale (CEA/CNRS/UJF), 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France. Tel.: +33 4 38 78 95 69; Fax: +33 4 38 78 54 94; E-mail: weik@ibs.fr Received 7 November 2005; Accepted 8 May 2006; Published online 8 June 2006. |
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| Abstract |
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| Acetylcholinesterase (AChE) terminates nerve-impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter, acetylcholine. Substrate traffic in AChE involves at least two binding sites, the catalytic and peripheral anionic sites, which have been suggested to be allosterically related and involved in substrate inhibition. Here, we present the crystal structures of Torpedo californica AChE complexed with the substrate acetylthiocholine, the product thiocholine and a nonhydrolysable substrate analogue. These structures provide a series of static snapshots of the substrate en route to the active site and identify, for the first time, binding of substrate and product at both the peripheral and active sites. Furthermore, they provide structural insight into substrate inhibition in AChE at two different substrate concentrations. Our structural data indicate that substrate inhibition at moderate substrate concentration is due to choline exit being hindered by a substrate molecule bound at the peripheral site. At the higher concentration, substrate inhibition arises from prevention of exit of acetate due to binding of two substrate molecules within the active-site gorge. |
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| Keywords: acetylcholinesterase, enzyme catalysis, kinetic crystallography, substrate inhibition, substrate traffic |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHNature Structural Biology Correspondence (01 Nov 1996) Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site The EMBO Journal Article (02 Jan 2003) Structure of acetylcholinesterase complexed with the nootropic alkaloid, (?)-huperzine A Nature Structural Biology Article (01 Jan 1997) The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix The EMBO Journal Article (10 Nov 2004) |
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