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

Abstract

We have determined a high-resolution three-dimensional structure of α-conotoxin BuIA, a 13-residue peptide toxin isolated from Conus bullatus. Despite its unusual 4/4 disulfide bond layout α-conotoxin BuIA exhibits strong antagonistic activity at α6/α3β2β3, α3β2, and α3β4 nAChR subtypes like some α4/7 conotoxins. α-Conotoxin BuIA lacks the C-terminal β-turn present within the second disulfide loop of α4/7 conotoxins, having only a "pseudo ω-shaped" molecular topology. Nevertheless, it contains a functionally critical two-turn helix motif, a feature ubiquitously found in α4/7 conotoxins. Such an aspect seems mainly responsible for similarities in the receptor recognition profile of α-conotoxin BuIA to α4/7 conotoxins. Structural comparison of α-conotoxin BuIA with α4/7 conotoxins and α4/3 conotoxin ImI suggests that presence of the second helical turn portion of the two-turn helix motif in α4/7 and α4/4 conotoxins may be important for binding to the α3 and/or α6 subunit of nAChR.