Solution Structure of α-Conotoxin ImI by <SUP>1</SUP>H Nuclear Magnetic Resonance

α-Conotoxin ImI derives from the venom of Conus imperialis and is the first and only small-peptide ligand that selectively binds to the neuronal α<INF>7</INF> homopentameric subtype of the nicotinic acetylcholine receptor (nAChR). This receptor subtype is a possible drug target for several neurological disorders. The cysteines are connected in the pairs Cys2−Cys8 and Cys3−Cys12. To date it is the only α-conotoxin with a 4/3 residue spacing between the cysteines. The structure of ImI has been determined by ¹H NMR spectroscopy in aqueous solution. The NMR structure is of high quality, with a backbone pairwise rmsd of 0.34 Å for a family of 19 structures, and comprises primarily a series of nested β turns. Addition of organic solvent does not perturb the solution structure. The first eight residues of ImI are identical to the larger, but related, conotoxin EpI and adopt a similar structure, despite a truncated second loop. Residues important for binding of ImI to the α<INF>7</INF> nAChR are all clustered on one face of the molecule. Once further binding data for EpI and ImI are available, the ImI structure will allow for design of novel α<INF>7</INF> nAChR-specific agonists and antagonists with a wide range of potential pharmaceutical applications.