BIOLOGICAL-ACTIVITY AND 3-DIMENSIONAL STRUCTURE OF AN AGONIST ANALOG OF BOMBESIN

JMV635, a nonapeptide analog of the active terminal nonapeptide segmen t of bombesin, was tested for its ability to stimulate in vitro amylas e release from rat pancreatic acinar cells and to inhibit the binding of gastrin-releasing peptide to rat pancreatic acini. It was found to be a full agonist of bombesin and to recognize the bombesin receptor w ith moderate potency. The NMR proton assignments of JMV635 were achiev ed, and the conformations of JMV635 in aqueous solution and in trifluo roethanol at 297 K were determined using two-dimensional COSY, HOHAHA, NOESY and ROESY experiments. In trifluoroethanol, JMV635, like the ac tive part of bombesin, showed st partial cc-helical structure. These r esults were confirmed by circular dichroism and refined by restrained molecular dynamic methods. Structure calculations, using the distance and angle restraints obtained from NMR data on TMV635, gave a total of 75 structures which could be aligned to a root mean square deviation of the bond length of 0.007 Angstrom, and of the valence angle of 1.55 degrees for the backbone atoms of the amino acid residues. The confor mation is a well-defined right-handed alpha-helix in the C-terminaI Q2 -G6 segment and is less structured in the three C-terminal residues. ( C) Munksgaard 1997.