Cys-loop receptors (CLRs) 2 belong to a class of ligandgated ion channels that are involved in fast synaptic transmission in the central nervous system and the neuromuscular junction. This transmission can either be excitatory or inhibitory depending on the charge of ions that pass through the ion conduction pathway of the channel. Excitatory transmission is mediated by nicotinic acetylcholine receptors (nAChR) and 5-HT 3 serotonin receptors, which selectively pass cations. On the other hand, inhibitory transmission is mediated by glycine receptors (GlyR) and ␥-aminobutyric acid (GABA A and GABA C ) receptors, which selectively conduct anions. In both types of receptors, the ion conduction pathway lies along the central axis formed by five channel subunits, which can either be identical for homomeric CLRs or non-identical for heteromeric CLRs. Opening and closing of the ion conduction pathway is controlled by a gate that is allosterically coupled to the extracellular ligand-binding domain (for a recent review see Ref. 1).Detailed structural data are still lacking for an intact eukaryotic CLR, but structural information has been obtained from 4 Å resolution electron microscopic images of the Torpedo nAChR (2) and higher resolution x-ray crystal structures of AChBP, a molluscan homolog of the extracellular domain of nAChRs (3, 4), the monomeric ␣1 nAChR subunit (5), and two prokaryotic homologs ELIC (6) and GLIC (7,8), which presumably represent the closed and open state of a CLR. Despite their different pharmacological properties, these CLRs share a common architectural arrangement of aromatic residues in their ligand-binding site. The ligand-binding site for CLRs is found at the interface between two subunits and ligands interact with amino acids from both the principal face (containing loops A, B, and C) and complementary face (containing loops D, E, and F). We have focused our attention on an aromatic residue that lies on the complementary face of the binding pocket and is highly conserved among eukaryotic and prokaryotic CLRs.Recently, we found that the tryptophan residue at position 55 of the rat ␣7 nAChR (Trp-55) was the site where synthetic * This research was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health, NIEHS (to E. A. G., J. C. S., and J. L. Y.), by G.0257.08), and the Belgian Federal Science Policy Office, Interuniversity Attraction Poles program (P6/31) (to J. T.), EU FP7 2020288 NeuroCypres (to C. U., A. B. S., and R. C. vd. S.), and KULeuven Onderzoekstoelage OT/08/048 (to S. V. S. and C. U.). □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1. The atomic coordinates and structure factors (codes 2XZ6 and 2XZ5)
