Solution structure of the cardiostimulant polypeptide anthopleurin-B and comparison with anthopleurin-A

Structure. 1995 Aug 15;3(8):791-803. doi: 10.1016/s0969-2126(01)00214-3.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cardiotonic Agents / chemistry*
  • Computer Graphics
  • Glycine
  • Hydrogen Bonding
  • Intercellular Signaling Peptides and Proteins
  • Isomerism
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Models, Structural
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Proline
  • Protein Conformation*
  • Protein Structure, Secondary*
  • Sea Anemones
  • Solutions
  • Structure-Activity Relationship

Substances

  • Cardiotonic Agents
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Solutions
  • anthopleurin-A
  • anthopleurin B
  • Proline
  • Glycine