Solution conformation of alpha-conotoxin GIC, a novel potent antagonist of alpha3beta2 nicotinic acetylcholine receptors

Abstract

α-Conotoxin GIC is a 16-residue peptide isolated from the venom of the cone snail Conus geographus. α-Conotoxin GIC potently blocks the α3β2 subtype of human nicotinic acetylcholine receptor, showing a high selectivity for neuronal versus muscle subtype [McIntosh, Dowell, Watkins, Garrett, Yoshikami, and Olivera (2002) J. Biol. Chem. 277, 33610–33615]. We have now determined the three-dimensional solution structure of α-conotoxin GIC by NMR spectroscopy. The structure of α-conotoxin GIC is well defined with backbone and heavy atom root mean square deviations (residues 2–16) of 0.53 Å and 0.96 Å respectively. Structure and surface comparison of α-conotoxin GIC with the other α4/7 subfamily conotoxins reveals unique structural aspects of α-conotoxin GIC. In particular, the structural comparison between α-conotoxins GIC and MII indicates molecular features that may confer their similar receptor specificity profile, as well as those that provide the unique binding characteristics of α-conotoxin GIC.