Solution structure of alpha-conotoxin ImI by 1H nuclear magnetic resonance.
alpha-Conotoxin ImI derives from the venom of Conus imperialis and is the first and only small-peptide ligand that selectively binds to the neuronal alpha7 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 alpha-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 A for a family of 19 structures, and comprises primarily a series of nested beta 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 alpha7 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 alpha7 nAChR-specific agonists and antagonists with a wide range of potential pharmaceutical applications.
Centre for Drug Design and Development, University of Queensland, Brisbane, Queensland 4072, Australia.
J
J
Gehrmann
N L
NL
Daly
P F
PF
Alewood
D J
DJ
Craik
D000595:Amino Acid Sequence; D020916:Conotoxins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D011522:Protons
D020916:Conotoxins; D008978:Mollusk Venoms; D009842:Oligopeptides; D011522:Protons; C087686:alpha-conotoxin ImI