The Cys-loop receptor super-family of neurotransmitter-gated ion channels mediates fast synaptic transmission throughout the human nervous system. These receptors exhibit widely varying pharmacologies, yet their structural characterization has relied heavily on their homology with the naturally abundant muscle-type Torpedo nicotinic acetylcholine receptor. Here we examine for the first time the structure of a human alpha 4 beta 2 neuronal nicotinic acetylcholine receptor. We show that human alpha 4 beta 2 nicotinic receptors adopt a secondary/tertiary fold similar to that of the Torpedo nicotinic receptor with a large proportion of both alpha-helix and beta-sheet, but exhibit a substantially increased thermal stability. Both receptors bind agonist, but with different patterns of agonist recognition -particularly in the nature of the interactions between aromatic residues and the agonist quaternary amine functional group. By comparing alpha 4 beta 2 and Torpedo receptors, we begin to delineate their structural similarities and differences. (C) 2011 Elsevier Inc. All rights reserved.