Download MendeleyCrystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA
Suno, R., Kimura, K.T., Nakane, T., Yamashita, K., Wang, J., Fujiwara, T., Yamanaka, Y., Im, D., Horita, S., Tsujimoto, H., Tawaramoto, M.S., Hirokawa, T., Nango, E., Tono, K., Kameshima, T., Hatsui, T., Joti, Y., Yabashi, M., Shimamoto, K., Yamamoto, M., Rosenbaum, D.M., Iwata, S., Shimamura, T., Kobayashi, T.(2018) Structure 26: 7-19.e5
- PubMed: 29225076
- DOI: https://doi.org/10.1016/j.str.2017.11.005
- Primary Citation of Related Structures:
5WQC, 5WS3 - PubMed Abstract:
Orexin peptides in the brain regulate physiological functions such as the sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using serial femtosecond crystallography and multi-crystal data collection with a synchrotron light source, we determined structures of human orexin 2 receptor in complex with the subtype-selective?antagonist EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) at 2.30-? and 1.96-? resolution. In comparison with the non-subtype-selective antagonist suvorexant, EMPA contacted fewer residues through hydrogen bonds at the orthosteric site, explaining the faster dissociation rate. Comparisons among these OX 2 R structures in complex with selective antagonists and previously determined OX 1 R/OX 2 R structures bound to non-selective antagonists revealed that the residue at positions 2.61?and 3.33 were critical for the antagonist selectivity in OX 2 R. The importance of these residues for binding selectivity to OX 2 R was also revealed by molecular dynamics simulation. These results should facilitate the development of antagonists for orexin receptors.
Organizational Affiliation:
Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
