THE 1.1 ANGSTROM CRYSTAL-STRUCTURE OF THE NEURONAL ACETYLCHOLINE-RECEPTOR ANTAGONIST, ALPHA-CONOTOXIN PNIA FROM CONUS-PENNACEUS

Background: alpha-Conotoxins are peptide toxins, isolated from Conus s nails, that block the nicotinic acetylcholine receptor (nAChR). The 16 -residue peptides PnlA and PnlB from Conus pennaceus incorporate the s ame disulfide framework as other alpha-conotoxins but differ in functi on from most alpha-conotoxins by blocking the neuronal nAChR, rather t han the skeletal muscle subtype. The crystal structure determination o f PnlA was undertaken to identify structural and surface features that might be important for biological activity. Results: The 1.1 Angstrom crystal structure of synthetic PnlA was determined by direct methods using the Shake-and-Bake program. The three-dimensional structure inco rporates a beta turn followed by two alpha-helical turns. The conforma tion is stabilised by two disulfide bridges that form the interior of the molecule, with all other side chains oriented outwards. Conclusion s: The compact architecture of the PnlA toxin provides a rigid framewo rk for presentation of chemical groups that are required for activity. The structure is characterized by distinct hydrophobic and polar surf aces; a 16 Angstrom separation of the sole positive and negative charg es (these two charged residues being located at opposite ends of the m olecule); a hydrophobic region and a protruding tyrosine side chain. T hese features may be important for the specific interaction of PnlA wi th neuronal nAChR.