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J. Biol. Chem., Vol. 280, Issue 28, 26457-26466, July 15, 2005

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Crystal Structure of Acetylcholine-binding Protein from Bulinus truncatus Reveals the Conserved Structural Scaffold and Sites of Variation in Nicotinic Acetylcholine Receptors^*

Patrick H. N. Celie, Remco V. Klaassen¶, Sarah E. van Rossum-Fikkert, René van Elk¶, Pim van Nierop¶, August B. Smit¶, and Titia K. Sixma||

From the Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands and ^¶Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Faculty of Earth and Life Sciences, Vrije Universiteit, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands

The crystal structure of acetylcholine-binding protein (AChBP) from the mollusk Lymnaea stagnalis is the established model for the ligand binding domains of the ligand-gated ion channel family, which includes nicotinic acetylcholine, 5-hydroxytryptamine (5-HT₃), -aminobutyric acid (GABA), types A and C, and glycine receptors. Here we present the crystal structure of a remote homolog, AChBP from Bulinus truncatus, which reveals both the conserved structural scaffold and the sites of variation in this receptor family. These include rigid body movements of loops that are close to the transmembrane interface in the receptors and changes in the intermonomer contacts, which alter the pentamer stability drastically. Structural, pharmacological and mutational analysis of both AChBPs shows how 3 amino acid changes in the binding site contribute to a 5-10-fold difference in affinity for nicotinic ligands. Comparison of these structures will be valuable for improving structure-function studies of ligand-gated ion channel receptors, including signal transduction, homology modeling, and drug design.

Received for publication, December 22, 2004 , and in revised form, April 25, 2005.

The atomic coordinates and structure factors (code 2BJ0) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) CAC69294and CAC69295

^* This work was supported by STW (Stichting Technische Weten-schappen), Project BBC6035, by the Netherlands Organization for Research in Chemistry (NWO-CW), Project 98016, and by EU-SPINE. 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.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 31-20-5121959; Fax: 31-205121954; E-mail: t.sixma{at}nki.nl.

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