Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA

Ryoji Suno, Kanako Terakado Kimura, Takanori Nakane, Keitaro Yamashita, Junmei Wang, Takaaki Fujiwara, Yasuaki Yamanaka, Dohyun Im, Shoichiro Horita, Hirokazu Tsujimoto, Maki S. Tawaramoto, Takatsugu Hirokawa, Eriko Nango, Kensuke Tono, Takashi Kameshima, Takaki Hatsui, Yasumasa Joti, Makina Yabashi, Keiko Shimamoto, Masaki YamamotoDaniel M. Rosenbaum, So Iwata, Tatsuro Shimamura, Takuya Kobayashi

Research output: Contribution to journalArticle

22 Scopus citations

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-Å and 1.96-Å 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 OX2R structures in complex with selective antagonists and previously determined OX1R/OX2R structures bound to non-selective antagonists revealed that the residue at positions 2.61 and 3.33 were critical for the antagonist selectivity in OX2R. The importance of these residues for binding selectivity to OX2R was also revealed by molecular dynamics simulation. These results should facilitate the development of antagonists for orexin receptors. Molecular dynamics simulations and structural information for orexin receptors indicates that the residues at positions 2.61 and 3.33 are critical for antagonist selectivity. Suno et al. determine the structure of a human GPCR using SACLA, and characterize differences between XFEL and synchrotron.

Original languageEnglish (US)
Pages (from-to)7-19.e5
JournalStructure
Volume26
Issue number1
DOIs
StatePublished - Jan 2 2018

Keywords

  • GPCR
  • X-ray crystallography
  • X-ray free-electron laser
  • orexin receptor
  • serial femtosecond crystallography
  • subtype selective ligand

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint Dive into the research topics of 'Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA'. Together they form a unique fingerprint.

  • Cite this

    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., ... Kobayashi, T. (2018). Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA. Structure, 26(1), 7-19.e5. https://doi.org/10.1016/j.str.2017.11.005