Premium
Orexin‐A is composed of a highly conserved C ‐terminal and a specific, hydrophilic N ‐terminal region, revealing the structural basis of specific recognition by the orexin‐1 receptor
Author(s) -
Takai Tomoyo,
Takaya Takao,
Nakano Mutsuko,
Akutsu Hideo,
Nakagawa Atsushi,
Aimoto Saburo,
Nagai Katsuya,
Ikegami Takahisa
Publication year - 2006
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.747
Subject(s) - orexin , chemistry , receptor , stereochemistry , helix (gastropod) , heteronuclear molecule , crystallography , neuropeptide , biochemistry , biology , nuclear magnetic resonance spectroscopy , ecology , snail
Orexins‐A and B, also called hypocretins‐1 and 2, respectively, are neuropeptides that regulate feeding and sleep‐wakefulness by binding to two orphan G protein‐coupled receptors named orexin‐1 (OX 1 R) and orexin‐2 (OX 2 R). The sequences and functions of orexins‐A and B are similar to each other, but the high sequence homology (68%) is limited in their C ‐terminal half regions (residues 15–33). The sequence of the N ‐terminal half region of orexin‐A (residues 1–14), containing two disulfide bonds, is very different from that of orexin‐B. The structure of orexin‐A was determined using two‐dimensional homonuclear and 15 N and 13 C natural abundance heteronuclear NMR experiments. Orexin‐A had a compact conformation in the N ‐terminal half region, which contained a short helix (III:Cys6‐Gln9) and was fixed by the two disulfide bonds, and a helix‐turn‐helix conformation (I:Leu16‐Ala23 and II:Asn25‐Thr32) in the remaining C ‐terminal half region. The C ‐terminal half region had both hydrophobic and hydrophilic residues, which existed on separate surfaces to provide an amphipathic character in helices I and II. The nine residues on the hydrophobic surface are also well conserved in orexin‐B, and it was reported that the substitution of each of them with alanine resulted in a significant drop in the functional potency at the receptors. Therefore, we suggest that they form the surface responsible for the main hydrophobic interaction with the receptors. On the other hand, the residues on the hydrophilic surface, together with the hydrophilic residues in the N ‐terminal half region that form a cluster, are known to make only small contributions to the binding to the receptors through similar alanine‐scan experiments. However, since our structure of orexin‐A showed that large conformational and electrostatical differences between orexins‐A and B were rather concentrated in the N ‐terminal half regions, we suggest that the region of orexin‐A is important for the preference for orexin‐A of OX 1 R. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.