title: Solution structure of the cardiostimulant polypeptide anthopleurin-B and comparison with anthopleurin-A.
abstract: BACKGROUND
  The polypeptide anthopleurin-B (AP-B) is one of a number of related toxins produced by sea anemones. AP-B delays inactivation of the voltage-gated sodium channel of excitable tissue. In the mammalian heart, this effect is manifest as an increase in the force of contraction. As a result, there is interest in exploiting the anthopleurins as lead compounds in the design of novel cardiac stimulants. Essential to this endeavour is a high-resolution solution structure of the molecule describing the positions of functionally important side chains.
  
  
  RESULTS
  AP-B exists in multiple conformations in solution as a result of cis-trans isomerization about the Gly40-Pro41 peptide bond. The solution structure of the major conformer of AP-B has been determined by two-dimensional 1H NMR at pH 4.5 and 25 degrees C. The core structure is a four-stranded, antiparallel beta-sheet (residues 2-4, 20-23, 34-37 and 45-48) and includes several beta-turns (6-9, 25-28, 30-33). Three loops connect the beta-strands, the longest and least well defined being the first loop, extending from residues 8-17. These features are shared by other members of this family of sea anemone toxins. The locations of a number of side chains which are important for the cardiac stimulatory activity of AP-B are well defined in the structures.
  
  
  CONCLUSIONS
  We have described the solution structure of AP-B and compared it with that of AP-A, from which it differs by substitutions at seven amino acid positions. It shares an essentially identical fold with AP-A yet is about 10-fold more active. Comparison of the structures, particularly in the region of residues essential for activity, gives a clearer indication of the location and extent of the cardioactive pharmacophore in these polypeptides.
authors.affiliation: NMR Laboratory, Biomolecular Research Institute, Parkville, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Monks
authors.forename: P K
authors.initials: PK
authors.lastname: Pallaghy
authors.forename: M J
authors.initials: MJ
authors.lastname: Scanlon
authors.forename: R S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry*; D003196:Computer Graphics; D005998:Glycine; D006860:Hydrogen Bonding; D036341:Intercellular Signaling Peptides and Proteins; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008961:Models, Structural; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011392:Proline; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012615:Sea Anemones; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D002316:Cardiotonic Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D012996:Solutions; C012746:anthopleurin-A; C026132:anthopleurin B; D011392:Proline; D005998:Glycine