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

15 Citations (Scopus)

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

Fingerprint

Orexin Receptors
Synchrotrons
Molecular Dynamics Simulation
Dissociative Disorders
Crystallography
Toluene
Sleep Initiation and Maintenance Disorders
Hydrogen
Sleep
Light
Peptides
Brain
Pharmaceutical Preparations
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Suno, R., Kimura, K. T., Nakane, T., Yamashita, K., Wang, J., Fujiwara, T., ... 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

Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA. / Suno, Ryoji; Kimura, Kanako Terakado; Nakane, Takanori; Yamashita, Keitaro; Wang, Junmei; Fujiwara, Takaaki; Yamanaka, Yasuaki; Im, Dohyun; Horita, Shoichiro; Tsujimoto, Hirokazu; Tawaramoto, Maki S.; Hirokawa, Takatsugu; Nango, Eriko; Tono, Kensuke; Kameshima, Takashi; Hatsui, Takaki; Joti, Yasumasa; Yabashi, Makina; Shimamoto, Keiko; Yamamoto, Masaki; Rosenbaum, Daniel M.; Iwata, So; Shimamura, Tatsuro; Kobayashi, Takuya.

In: Structure, Vol. 26, No. 1, 02.01.2018, p. 7-19.e5.

Research output: Contribution to journalArticle

Suno, R, Kimura, KT, Nakane, T, Yamashita, K, Wang, J, Fujiwara, T, Yamanaka, Y, Im, D, Horita, S, Tsujimoto, H, Tawaramoto, MS, Hirokawa, T, Nango, E, Tono, K, Kameshima, T, Hatsui, T, Joti, Y, Yabashi, M, Shimamoto, K, Yamamoto, M, Rosenbaum, DM, Iwata, S, Shimamura, T & Kobayashi, T 2018, 'Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA', Structure, vol. 26, no. 1, pp. 7-19.e5. https://doi.org/10.1016/j.str.2017.11.005
Suno, Ryoji ; Kimura, Kanako Terakado ; Nakane, Takanori ; Yamashita, Keitaro ; Wang, Junmei ; Fujiwara, Takaaki ; Yamanaka, Yasuaki ; Im, Dohyun ; Horita, Shoichiro ; Tsujimoto, Hirokazu ; Tawaramoto, Maki S. ; Hirokawa, Takatsugu ; Nango, Eriko ; Tono, Kensuke ; Kameshima, Takashi ; Hatsui, Takaki ; Joti, Yasumasa ; Yabashi, Makina ; Shimamoto, Keiko ; Yamamoto, Masaki ; Rosenbaum, Daniel M. ; Iwata, So ; Shimamura, Tatsuro ; Kobayashi, Takuya. / Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA. In: Structure. 2018 ; Vol. 26, No. 1. pp. 7-19.e5.
@article{3278c38a37214415980ea3ae7836cb6f,
title = "Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA",
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-{\AA} and 1.96-{\AA} 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.",
keywords = "GPCR, orexin receptor, serial femtosecond crystallography, subtype selective ligand, X-ray crystallography, X-ray free-electron laser",
author = "Ryoji Suno and Kimura, {Kanako Terakado} and Takanori Nakane and Keitaro Yamashita and Junmei Wang and Takaaki Fujiwara and Yasuaki Yamanaka and Dohyun Im and Shoichiro Horita and Hirokazu Tsujimoto and Tawaramoto, {Maki S.} and Takatsugu Hirokawa and Eriko Nango and Kensuke Tono and Takashi Kameshima and Takaki Hatsui and Yasumasa Joti and Makina Yabashi and Keiko Shimamoto and Masaki Yamamoto and Rosenbaum, {Daniel M.} and So Iwata and Tatsuro Shimamura and Takuya Kobayashi",
year = "2018",
month = "1",
day = "2",
doi = "10.1016/j.str.2017.11.005",
language = "English (US)",
volume = "26",
pages = "7--19.e5",
journal = "Structure with Folding & design",
issn = "0969-2126",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA

AU - Suno, Ryoji

AU - Kimura, Kanako Terakado

AU - Nakane, Takanori

AU - Yamashita, Keitaro

AU - Wang, Junmei

AU - Fujiwara, Takaaki

AU - Yamanaka, Yasuaki

AU - Im, Dohyun

AU - Horita, Shoichiro

AU - Tsujimoto, Hirokazu

AU - Tawaramoto, Maki S.

AU - Hirokawa, Takatsugu

AU - Nango, Eriko

AU - Tono, Kensuke

AU - Kameshima, Takashi

AU - Hatsui, Takaki

AU - Joti, Yasumasa

AU - Yabashi, Makina

AU - Shimamoto, Keiko

AU - Yamamoto, Masaki

AU - Rosenbaum, Daniel M.

AU - Iwata, So

AU - Shimamura, Tatsuro

AU - Kobayashi, Takuya

PY - 2018/1/2

Y1 - 2018/1/2

N2 - 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.

AB - 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.

KW - GPCR

KW - orexin receptor

KW - serial femtosecond crystallography

KW - subtype selective ligand

KW - X-ray crystallography

KW - X-ray free-electron laser

UR - http://www.scopus.com/inward/record.url?scp=85039856148&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039856148&partnerID=8YFLogxK

U2 - 10.1016/j.str.2017.11.005

DO - 10.1016/j.str.2017.11.005

M3 - Article

C2 - 29225076

AN - SCOPUS:85039856148

VL - 26

SP - 7-19.e5

JO - Structure with Folding & design

JF - Structure with Folding & design

SN - 0969-2126

IS - 1

ER -