We have determined a high-resolution three-dimensional structure of alpha-conotoxin BuIA, a 13-residue peptide toxin isolated from Conus bullatus. Despite its unusual 4/4 disulfide bond layout alpha-conotoxin BuIA exhibits strong antagonistic activity at alpha 6/alpha 3 beta 2 beta 3, alpha 3 beta 2, and alpha 3 beta P4 nAChR subtypes like some alpha 4/7 conotoxins. alpha-Conotoxin BuIA lacks the C-terminal beta-turn present within the second disulfide loop of a4/7 conotoxins, having only a "pseudo omega-shaped" molecular topology. Nevertheless, it contains a functionally critical two-turn helix motif, a feature ubiquitously found in alpha 4/7 conotoxins. Such an aspect seems mainly responsible for similarities in the receptor recognition profile of alpha-conotoxin BuIA to alpha 4/7 conotoxins. Structural comparison of of alpha-conotoxin BuIA with alpha 4/7 conotoxins and alpha 4/3 conotoxin ImI suggests that presence of the second helical turn portion of the two-turn helix motif in alpha 4/7 and alpha 4/4 conotoxins may be important for binding to the alpha 3 and/or alpha 6 subunit of nAChR. (c) 2006 Elsevier Inc. All rights reserved.