Conformation of a peptide ligand bound to its G-protein coupled receptor

Many peptide hormones elicit a wide array of physiological effects by bindi ng to G-protein coupled receptors. We have determined the conformation of p ituitary adenylate cyclase activating polypeptide, PACAP(I-ZI)NH2, bound to a PACAP-specific receptor by NMR spectroscopy. Residues 3-7 form a unique beta -coil structure that is preceded by an N-terminal extended tail. This beta -coil creates a patch of hydrophobic residues that is important for re ceptor binding. In contrast, the C-terminal region (residues 8-21) forms an ct-helix, similar to that in the micelle-bound PACAP. Thus, the conformati onal difference between PACAP in the receptor-bound and the micelle-bound s tates is limited to the N-terminal seven residues. This observation is cons istent with the two-step ligand transportation model in which PACAP first b inds to the membrane nonspecifically and then diffuses two-dimensionally in search of its receptor; a conformational change at the N-terminal region t hen allows specific interactions between the ligand and the receptor.