Models for the A- and B-receptor-bound conformations of CCK-8

Energy calculations were performed for CCK-8 (Asp26-Tyr(SO3)27-Met28-Gly29- Trp30-Met31-Asp32-Phe33-NH2, I) and [desaminoTyr(SO3)27, Nle28,31]CCK-7 (II), which are nonselective ligands of CCK receptors, and for the CCK-A selective analog [desaminoTyr(SO3)27, Nle28,31, N-Me-Asp32]CCK-7 (III) and the CCK-B selective analog [desaminoTyr(SO3)27, Nle28, N-Me-Leu31]CCK-7 (IV). The geometrical shapes of the obtained low energy backbone conformers were then compared with each other, searching for similar spatial arrangements of specific atomic centers. The comparisons were performed separately for peptides with high affinity towards CCK receptors of the A type (compounds I, II and III) and for peptides with high affinity towards CCK receptors of the B type (compounds I, II and IV). Possible models for CCK "A"- and "B"-receptor-bound conformations were then developed. The proposed CCK "B-conformation" has a distorted beta-III turn at the C-terminal Gly-Trp-Met-Asp fragment, the Phe33 residue and the C-terminal amide being directed outward from the turn. The CCK "A-conformation" has two reversals of the peptide chain so that the C alpha-atoms of the C-terminal pentapeptide appear at the corners of a nearly regular pentagon, and a distinct beta-II turn is centered at the N-terminal Tyr-Met-Gly-Trp fragment, the planes of the turn and the pentagon being almost perpendicular. The proposed models are consistent with the results of biological testing for CCK related peptides including cyclic analogs and CCK-A selective tetrapeptides.