7L1U

Orexin Receptor 2 (OX2R) in Complex with G Protein and Natural Peptide-Agonist Orexin B (OxB)

Summary for 7L1U

• Entry DOI: 10.2210/pdb7l1u/pdb
• Related: 7L1V
• EMDB information: 23118 23119
• Descriptor: Engineered Guanine nucleotide-binding protein subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: class a gpcr, orexin receptor 2, ox2r, membrane protein, peptide agonist
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 147448.96

Authors

Hong, C.,Byrne, N.J.,Zamlynny, B.,Tummala, S.,Xiao, L.,Shipman, J.M.,Partridge, A.T.,Minnick, C.,Breslin, M.J.,Rudd, M.T.,Stachel, S.J.,Rada, V.L.,Kern, J.C.,Armacost, K.A.,Hollingsworth, S.A.,O'Brien, J.A.,Hall, D.L.,McDonald, T.P.,Strickland, C.,Brooun, A.,Soisson, S.M.,Hollenstein, K. (deposition date: 2020-12-15, release date: 2021-02-10, Last modification date: 2024-11-20)

Primary citation

Hong, C.,Byrne, N.J.,Zamlynny, B.,Tummala, S.,Xiao, L.,Shipman, J.M.,Partridge, A.T.,Minnick, C.,Breslin, M.J.,Rudd, M.T.,Stachel, S.J.,Rada, V.L.,Kern, J.C.,Armacost, K.A.,Hollingsworth, S.A.,O'Brien, J.A.,Hall, D.L.,McDonald, T.P.,Strickland, C.,Brooun, A.,Soisson, S.M.,Hollenstein, K.
Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.
Nat Commun, 12:815-815, 2021

PubMed 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 (OXR) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OXR agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OXR bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OXR to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OXR 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.

PubMed: 33547286
DOI: 10.1038/s41467-021-21087-6

Experimental method

ELECTRON MICROSCOPY (3.2 Å)