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| Subject Categories: Structural Biology | Membranes & Transport |
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| The EMBO Journal
(2003) 22, 1–12, doi:10.1093/emboj/cdg005 |
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| Structural insights into ligand interactions at the acetylcholinesterase peripheral anionic site |
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Yves Bourne1, Palmer Taylor2, Zoran Radi 2 and Pascale Marchot3
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1 Architecture et Fonction des Macromolécules Biologiques, CNRS UMR 6098, 31 Chemin Joseph Aiguier, F-13402 Marseille Cedex 20, France 2 Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0636, USA 3 Ingénierie des Protéines, CNRS UMR 6560, Institut Fédératif de Recherche Jean Roche, Université de la Méditerranée, Faculté de Médecine Secteur Nord, F-13916 Marseille Cedex 20, France To whom correspondence should be addressed Yves Bourne, yves@afmb.cnrs-mrs.fr Pascale Marchot, marchot.p@jean-roche.univ-mrs.fr Received 13 August 2002; Revised 31 October 2002; Accepted 1 November 2002. |
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| Abstract |
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| The peripheral anionic site on acetylcholinesterase (AChE), located at the active center gorge entry, encompasses overlapping binding sites for allosteric activators and inhibitors; yet, the molecular mechanisms coupling this site to the active center at the gorge base to modulate catalysis remain unclear. The peripheral site has also been proposed to be involved in heterologous protein associations occurring during synaptogenesis or upon neurodegeneration. A novel crystal form of mouse AChE, combined with spectrophotometric analyses of the crystals, enabled us to solve unique structures of AChE with a free peripheral site, and as three complexes with peripheral site inhibitors: the phenylphenanthridinium ligands, decidium and propidium, and the pyrogallol ligand, gallamine, at 2.20–2.35 Å resolution. Comparison with structures of AChE complexes with the peptide fasciculin or with organic bifunctional inhibitors unveils new structural determinants contributing to ligand interactions at the peripheral site, and permits a detailed topographic delineation of this site. Hence, these structures provide templates for designing compounds directed to the enzyme surface that modulate specific surface interactions controlling catalytic activity and non-catalytic heterologous protein associations. |
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| Keywords: acetylcholinesterase structure, allosteric inhibitor, peripheral anionic site, phenanthridinium inhibitors, surface interaction |
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