1WSO

The solution structures of human Orexin-A

1WSO の概要

• エントリーDOI: 10.2210/pdb1wso/pdb
• 関連するPDBエントリー: 1CQ0 1R02
• NMR情報: BMRB: 5994
• 分子名称: Orexin-A (1 entity in total)
• 機能のキーワード: hypocretin, orexin, gpcr, orphan g-protein coupled receptor, narcolepsy, neuropeptide
• 由来する生物種: Homo sapiens (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 3569.17

構造登録者

Ikegami, T.,Takai, T. (登録日: 2004-11-08, 公開日: 2004-11-30, 最終更新日: 2024-10-23)

主引用文献

Takai, T.,Takaya, T.,Nakano, M.,Akutsu, H.,Nakagawa, A.,Aimoto, S.,Nagai, K.,Ikegami, T.
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
J.Pept.Sci., 12:443-454, 2006

PubMed Abstract: 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.

PubMed: 16429482
DOI: 10.1002/psc.747

実験手法

SOLUTION NMR