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Journal of Biochemistry Advance Access published online on April 24, 2007
Journal of Biochemistry, doi:10.1093/jb/mvm100
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© 2007 The Japanese Biochemical Society

Structural modeling and mutation analysis of a nociceptin receptor and its ligand complexes

Natsuyo Akuzawa1), Shigeki Takeda*,1) and Masaji Ishiguro2)

1)Department of Nano-Material Systems, Graduate School of Engineering, Gunma University, 1-5-1 Tenjin-cho, Kiryu, Gunma 376-8515, JAPAN
2)Suntory Institute for Bioorganic Research, 1-1 Wakayamadai, Shimamoto, Osaka 618-8503, JAPAN

*)Correspondence to: Shigeki Takeda: Department of Nano-Material Systems, Graduate School of Engineering, Gunma University, 1-5-1 Tenjin-cho, Kiryu, Gunma 376-8515, JAPAN. Tel: +81-277-30-1434, Fax: +81-277-30-1434, E-mail: stakeda{at}bce.gunma-u.ac.jp

Received December 27, 2006; Accepted April 9, 2007


  Abstract

We recently modeled and proposed four ligand-bound conformations for a G-protein-coupled receptor, namely, forms I, II, III, and IV, based on the three-dimensional structure and functional evidences for rhodopsin. In this study, the same strategy was applied to a human nociceptin receptor (NR) in order to predict ligand-bound receptor structures. Additionally, site-directed mutagenesis studies were carried out to evaluate these structures. A Thr138Ala mutant demonstrated the same affinity for [Phe1{Psi}(CH2-NH)Gly2]nociceptin(1-13)NH2 as the wild-type receptor; however, the affinity of this mutant for nociceptin was 20-fold lower than that of the wild type. A Ser223Ala mutation showed the same characteristics as those of the wild type. On the other hand, a Gln280Ala mutation reduced the affinity to nociceptin by more than 60-folds. These results suggested that a change in the conformation of NR following agonist binding did not accompany the rigid-body rotation of the 6th transmembrane segment that was reported for an adrenergic receptor and a {kappa}-opioid receptor. NR is potently activated not only by nociceptin but also a synthetic peptide, i.e., Ac-RYYRIK-NH2, although the amino acid sequences of both these ligands are completely different. The model explains why both the ligands activate NR and shows that their receptor-bound conformations have similar three-dimensional structurese.

Key Words: G-protein-coupled receptor, nociceptin receptor, modeling, site-directed mutagenesis


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