Nuclear magnetic resonance solution conformation of α-conotoxin AuIB, an α3β4 subtype-selective neuronal nicotinic acetylcholine receptor antagonist

Abstract

The neuronal nicotinic acetylcholine receptors constitute a highly diverse group, with subtypes consisting of pentameric combinations of α and β subunits, α-Conotoxins are a homologous series of small peptides that antagonize these receptors. We present the three-dimensional solution structure of α-conotoxin AuIB, the first 15-residue α-conotoxin known to selectively block the α3β4 nicotinic acetylcholine receptor subtype. The pair- wise backbone and heavy-atom root mean square deviation for an ensemble of 20 structures are 0.269 and 0.720 respectively. The overall fold of α- conotoxin AuIB closely resembles that of the α4/7 subfamily α-conotoxins. However, the absence of Tyr15, normally present in other α4/7 members, results in tight bending of the backbone at the C terminus and effectively renders Asp14 to assume the spatial location of Tyr15 present in other neuronal α4/7 α-conotoxins. Structural comparison of α-conotoxin AuIB with the α3β2 subtype-specific α-conotoxin MII shows different electrostatic surface charge distributions, which may be important in differential receptor subtype recognition.