Conformation of a peptide ligand bound to its G-protein coupled receptor.
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.
Inooka
H
H
Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan. Inooka_Hiroshi@takeda.co.jp
Ohtaki
T
T
Kitahara
O
O
Ikegami
T
T
Endo
S
S
Kitada
C
C
Ogi
K
K
Onda
H
H
Fujino
M
M
Shirakawa
M
M
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
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