THE SOLUTION STRUCTURE OF SARAFOTOXIN-C - IMPLICATIONS FOR LIGAND RECOGNITION BY ENDOTHELIN

The solution structure of sarafotoxin-c has been determined using NMR spectroscopy. A total of 112 interproton distance constraints derived from two-dimensional MMR spectra were used to calculate a family of st ructures using a combination of distance geometry and dynamical simula ted annealing calculations. The structures reveal a well defined cu he lix extending from Glu(9) to Cys(15) and an N-terminal region (Cys(1)- Asp(8)) that is tightly constrained by disulfide bands to Cys residues in the central helix. In contrast, the C-terminal region (His(16)-Trp (21)) does not adopt a defined conformation in the final family of str uctures. This is consistent with the paucity of NMR-derived structural constraints obtained for this region and leads to the suggestion that the C-terminal region oscillates rapidly between a number of substant ially different conformers. It is proposed that differences between th e central helix of the endothelin and sarafotoxin isopeptides might be important in binding of these ligands by the G protein-coupled endoth elin receptors.