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

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, Vanessa L. Rada, Jeffrey C. Kern, Kira A. Armacost, Scott A. Hollingsworth, Julie A. O’Brien, Dawn L. Hall, Terrence P. McDonald, Corey Strickland, Alexei Brooun, Stephen M. Soisson () and Kaspar Hollenstein ()
Additional contact information
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

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21087-6

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DOI: 10.1038/s41467-021-21087-6

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