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

Nature Structural Biology volume 8, pages 161–165 (2001)Cite this article

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)NH2, bound to a PACAP-specific receptor by NMR spectroscopy. Residues 3–7 form a unique β-coil structure that is preceded by an N-terminal extended tail. This β-coil creates a patch of hydrophobic residues that is important for receptor binding. In contrast, the C-terminal region (residues 8–21) forms an α-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.

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Figure 1: Receptor binding of PACAP27 and PACAP21 and GTP-γS binding induced by receptor activation.
Figure 2: TRNOE between aliphatic and aromatic protons in NOESY spectra.
Figure 3: Stereo views of the PACAP peptides.
Figure 4: The N-terminal β-coil structure of the receptor-bound PACAP21.

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Acknowledgements

We thank K. Wakamatsu, Y. Kyogoku, H. Akutsu, Y. Yamamoto and M. Waelchli for helpful discussions. This research was supported by the Ministry of Education, Science, Sports and Culture of Japan.

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Authors and Affiliations

  1. Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, 630-0101, Nara, Japan

    Hiroshi Inooka, Takahisa Ikegami & Masahiro Shirakawa

  2. Pharmaceutical Discovery Research Division, Discovery Research Laboratories V, Takeda Chemical Industries Ltd., 17-85 Juso Honmachi 2, Yodogawa-Ku, 532-8686, Osaka, Japan

    Hiroshi Inooka, Satoshi Endo & Masahiko Fujino

  3. Pharmaceutical Discovery Research Division, Discovery Research Laboratories I, Takeda Chemical Industries Ltd., Wadai 10, Tsukuba, 300-4293, Ibaraki, Japan

    Tetsuya Ohtaki, Osamu Kitahara, Chieko Kitada, Kazuhiro Ogi, Haruo Onda & Masahiko Fujino

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  1. Hiroshi Inooka
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Correspondence to Hiroshi Inooka or Masahiro Shirakawa.

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Inooka, H., Ohtaki, T., Kitahara, O. et al. Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat Struct Mol Biol 8, 161–165 (2001). https://doi.org/10.1038/84159

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