title: Conformation of a peptide ligand bound to its G-protein coupled receptor.
abstract: Many peptide hormones elicit a wide array of physiological effects by binding to G-protein coupled receptors. We have determined the conformation of pituitary adenylate cyclase activating polypeptide, PACAP(1--21)NH(2), 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 receptor binding. In contrast, the C-terminal region (residues 8--21) forms an alpha-helix, similar to that in the micelle-bound PACAP. Thus, the conformational difference between PACAP in the receptor-bound and the micelle-bound states is limited to the N-terminal seven residues. This observation is consistent with the two-step ligand transportation model in which PACAP first binds to the membrane nonspecifically and then diffuses two-dimensionally in search of its receptor; a conformational change at the N-terminal region then allows specific interactions between the ligand and the receptor.
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan. Inooka_Hiroshi@takeda.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Inooka
authors.forename: T
authors.initials: T
authors.lastname: Ohtaki
authors.forename: O
authors.initials: O
authors.lastname: Kitahara
authors.forename: T
authors.initials: T
authors.lastname: Ikegami
authors.forename: S
authors.initials: S
authors.lastname: Endo
authors.forename: C
authors.initials: C
authors.lastname: Kitada
authors.forename: K
authors.initials: K
authors.lastname: Ogi
authors.forename: H
authors.initials: H
authors.lastname: Onda
authors.forename: M
authors.initials: M
authors.lastname: Fujino
authors.forename: M
authors.initials: M
authors.lastname: Shirakawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D008024:Ligands; D008823:Micelles; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone / Q000737:chemistry / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D012756:Sheep; D018411:Spodoptera
chemical_list: D008024:Ligands; D008823:Micelles; D009479:Neuropeptides; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D011979:Receptors, Pituitary Hormone; D020962:Heterotrimeric GTP-Binding Proteins