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Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation

Author

Listed:
  • Chuan Hong

    (MRL, Merck & Co., Inc)

  • Noel J. Byrne

    (MRL, Merck & Co., Inc)

  • Beata Zamlynny

    (MRL, Merck & Co., Inc)

  • Srivanya Tummala

    (MRL, Merck & Co., Inc)

  • Li Xiao

    (MRL, Merck & Co., Inc)

  • Jennifer M. Shipman

    (MRL, Merck & Co., Inc)

  • Andrea T. Partridge

    (MRL, Merck & Co., Inc)

  • Christina Minnick

    (MRL, Merck & Co., Inc)

  • Michael J. Breslin

    (MRL, Merck & Co., Inc)

  • Michael T. Rudd

    (MRL, Merck & Co., Inc)

  • Shawn J. Stachel

    (MRL, Merck & Co., Inc)

  • Vanessa L. Rada

    (MRL, Merck & Co., Inc)

  • Jeffrey C. Kern

    (MRL, Merck & Co., Inc)

  • Kira A. Armacost

    (MRL, Merck & Co., Inc)

  • Scott A. Hollingsworth

    (MRL, Merck & Co., Inc.)

  • Julie A. O’Brien

    (MRL, Merck & Co., Inc)

  • Dawn L. Hall

    (MRL, Merck & Co., Inc)

  • Terrence P. McDonald

    (MRL, Merck & Co., Inc)

  • Corey Strickland

    (MRL, Merck & Co., Inc)

  • Alexei Brooun

    (MRL, Merck & Co., Inc)

  • Stephen M. Soisson

    (MRL, Merck & Co., Inc)

  • Kaspar Hollenstein

    (MRL, Merck & Co., Inc)

Abstract

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain’s ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

Suggested Citation

  • Chuan Hong & Noel J. Byrne & Beata Zamlynny & Srivanya Tummala & Li Xiao & Jennifer M. Shipman & Andrea T. Partridge & Christina Minnick & Michael J. Breslin & Michael T. Rudd & Shawn J. Stachel & Van, 2021. "Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21087-6
    DOI: 10.1038/s41467-021-21087-6
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    6. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Aika Iwama & Ryoji Kise & Hiroaki Akasaka & Fumiya K. Sano & Hidetaka S. Oshima & Asuka Inoue & Wataru Shihoya & Osamu Nureki, 2024. "Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    8. Youwen Zhuang & Lei Wang & Jia Guo & Dapeng Sun & Yue Wang & Weiyi Liu & H. Eric Xu & Cheng Zhang, 2022. "Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Chaehee Park & Jinuk Kim & Seung-Bum Ko & Yeol Kyo Choi & Hyeongseop Jeong & Hyeonuk Woo & Hyunook Kang & Injin Bang & Sang Ah Kim & Tae-Young Yoon & Chaok Seok & Wonpil Im & Hee-Jung Choi, 2022. "Structural basis of neuropeptide Y signaling through Y1 receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Shivani Sachdev & Brendan A. Creemer & Thomas J. Gardella & Ross W. Cheloha, 2024. "Highly biased agonism for GPCR ligands via nanobody tethering," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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