Nuclear magnetic resonance solution conformation of alpha-conotoxin AuIB, an alpha(3)beta(4) subtype-selective neuronal nicotinic acetylcholine receptor antagonist

The neuronal nicotinic acetylcholine receptors constitute a highly diverse group, with subtypes consisting of pentameric combinations of alpha and bet a subunits. alpha-Conotoxins are a homologous series of small peptides that antagonize these receptors, We present the three-dimensional solution stru cture of alpha-conotoxin AuIB, the first 15-residue alpha-conotoxin known t o selectively block the alpha(3)beta(4) nicotinic acetylcholine receptor su btype. The pairwise backbone and heavy-atom root mean square deviation for an ensemble of 20 structures are 0.269 and 0.720 Angstrom respectively. The overall fold of alpha-conotoxin AuIB closely resembles that of the alpha 4 /7 subfamily alpha-conotoxins. However, the absence of Tyr(15), normally pr esent in other alpha 4/7 members, results in tight bending of the backbone at the C terminus and effectively renders Asp(14) to assume the spatial loc ation of Tyr(15) present in other neuronal alpha 4/7 alpha-conotoxins. Stru ctural comparison of alpha-conotoxin AuIB with the alpha(3)beta(2) Subtype- specific alpha-conotoxin MII shows different electrostatic surface charge d istributions, which may be important in differential receptor subtype recog nition.