NMR structure determination of α-conotoxin BuIA, a novel neuronal nicotinic acetylcholine receptor antagonist with an unusual 4/4 disulfide scaffold (original) (raw)

We have determined a high-resolution three-dimensional structure of a-conotoxin BuIA, a 13-residue peptide toxin isolated from Conus bullatus. Despite its unusual 4/4 disulfide bond layout a-conotoxin BuIA exhibits strong antagonistic activity at a6/a3b2b3, a3b2, and a3b4 nAChR subtypes like some a4/7 conotoxins. a-Conotoxin BuIA lacks the C-terminal b-turn present within the second disulfide loop of a4/7 conotoxins, having only a ''pseudo x-shaped'' molecular topology. Nevertheless, it contains a functionally critical two-turn helix motif, a feature ubiquitously found in a4/7 conotoxins. Such an aspect seems mainly responsible for similarities in the receptor recognition profile of a-conotoxin BuIA to a4/7 conotoxins. Structural comparison of a-conotoxin BuIA with a4/7 conotoxins and a4/3 conotoxin ImI suggests that presence of the second helical turn portion of the two-turn helix motif in a4/7 and a4/4 conotoxins may be important for binding to the a3 and/or a6 subunit of nAChR.