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Y for acetylcholine, but greater affinity for the a7-specific antagonistic a-conotoxin peptides (Hansen et al, 2002, 2004; Celie et al, 2004). The coupling of AChBP with all the pore domain on the 5HT3A receptor not simply results in acetylcholine binding with modest or intermediate affinity, characteristic of activatable receptors, but also triggers a low frequency opening on the ion channel (Bouzat et al, 2004), arguing for AChBP to become each a structural and functional surrogate for the extracellular LBD of nAChRs. A refined electron microscopy structure from the heteropentameric muscle-type, a12bgd nAChR, solved in part2009 European Molecular Biology OrganizationThe pentameric acetylcholine-binding protein (AChBP) is usually a soluble surrogate in the ligand binding domain of nicotinic acetylcholine receptors. Agonists bind inside a nest of aromatic side chains contributed by loops C and F on opposing faces of every subunit interface. Crystal structures of Aplysia AChBP bound using the agonist anabaseine, two partial agonists selectively activating the a7 receptor, 3-(two,4-dimethoxybenzylidene)-anabaseine and its 4-hydroxy metabolite, and an indole-containing partial agonist, tropisetron, have been solved at two.7.75 A resolution. All structures determine the Trp 147 carbonyl oxygen as the hydrogen bond acceptor for the agonist-protonated nitrogen. In the partial agonist complexes, the benzylidene and indole substituent positions, dictated by tight interactions with loop F, preclude loop C from adopting the closed conformation seen for full agonists. Fluctuation in loop C position and duality in ligand binding orientations suggest molecular bases for partial agonism at full-length receptors. This study, though CD235 Biological Activity pointing to loop F as a major determinant of receptor subtype selectivity, also identifies a brand new template region for designing a7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative issues. The EMBO Journal (2009) 28, 3040051. doi:10.1038/ emboj.2009.227; Fmoc-NH-PEG3-CH2CH2COOH Epigenetic Reader Domain Published on-line 20 AugustCorresponding authors. Y Bourne, Architecture et Fonction des Macromolecules Biologiques, UMR-6098, Case 932 – Campus de Luminy-163 Avenue de Luminy, F-13288 Marseille Cedex 09. Tel.: 33 4 91 82 55 66; Fax: 33 4 91 26 67 20; E-mail: [email protected] or P Taylor, Division of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0657, USA. Tel.: 1 858 534 1366; Fax: 1 858 534 8248; E-mail: [email protected] five Present address: Vollum Institute, Oregon Wellness and Science University, Portland, OR, USA 6 Present address: Genomics Institute from the Novartis Analysis Foundation, La Jolla, CA, USA 7 These authors contributed equally to this function Received: 7 April 2009; accepted: 14 July 2009; published on-line: 20 August3040 The EMBO Journal VOL 28 | NO 19 |AChBP complexes with nicotinic partial agonists RE Hibbs et alusing the AChBP template (Unwin, 2005), as well as the crystal structure with the extracellular domain in the isolated muscletype a1 subunit bound towards the peptide antagonist, a-bungarotoxin (Dellisanti et al, 2007), confirms the close structural similarity between the AChBP and nAChR subunits. A current characterization of pentameric, prokaryotic LGICs shows their structural homology to AChBP and documents the similarity of their intra-subunit and inter-subunit arrangements (Bocquet et al, 2007, 2009; Hilf and Dutzler, 2008, 2009). To date, AChBP provides the ideal templ.