Orexin receptor type 2

Function

G protein-coupled receptor that binds neuropeptides orexin-A and orexin-B, two neuropeptides derived from a common precursor, prepro-orexin. Upon neuropeptide ligand binding, HCRTR2 can couple with both G(q)/11 and G(i)/o heterotrimeric G proteins thereby initiating distinct downstream signaling cascades. Involved in regulating the sleep-wake cycle (By similarity). Contributes to central regulation of glucose homeostasis (By similarity).

Classification

Family (Pfam)

PF00001 7tm_1, PF03827 Orexin_rec2

InterPro

GPCR_Rhodpsn, GPCR_Rhodpsn_7TM, Orexin_rcpt, Orexin_rcpt_2

Functional cluster

Membrane Transporters & GPCRs

Experimental structures · PDB · 11

• 4S0V X-ray 2.50A
• 5WQC X-ray 1.96A
• 5WS3 X-ray 2.30A
• 6TPG X-ray 2.74A
• 6TPJ X-ray 2.74A
• 6TPN X-ray 2.61A
• 7L1U EM 3.20A
• 7L1V EM 3.00A
• 7SQO EM 3.17A
• 7SR8 EM 3.30A
• 7XRR X-ray 2.89A

A predicted model is available from AlphaFold.

Gene Ontology · 14

• GO:0005886 plasma membrane
• GO:0045202 synapse
• GO:0008188 neuropeptide receptor activity
• GO:0016499 orexin receptor activity
• GO:0017046 peptide hormone binding
• GO:0032870 cellular response to hormone stimulus
• GO:0007268 chemical synaptic transmission
• GO:0022410 circadian sleep/wake cycle process
• GO:0007631 feeding behavior
• GO:0042593 glucose homeostasis
• GO:0040011 locomotion
• GO:0007218 neuropeptide signaling pathway
• GO:0010840 regulation of circadian sleep/wake cycle, wakefulness
• GO:0051480 regulation of cytosolic calcium ion concentration

Drugs targeting this protein · 8

• SUVOREXANT antagonist
• SB-649868 antagonist
• FILOREXANT antagonist
• LEMBOREXANT antagonist
• SELTOREXANT antagonist
• DARIDOREXANT antagonist
• ALMOREXANT antagonist
• DARIDOREXANT HYDROCHLORIDE antagonist

Related proteins · sequence + function similarity

• Orexin receptor type 2 1.00
• Orexin receptor type 2 1.00
• Orexin receptor type 2 0.99
• Orexin receptor type 2 0.99
• Neuropeptide FF receptor 2 0.92
• Neuropeptide FF receptor 2 0.92
• Orexin/Hypocretin receptor type 1 0.89
• Allatostatin-A receptor 0.88
• Orexin/Hypocretin receptor type 1 0.88
• Orexin/Hypocretin receptor type 1 0.88
• Neuropeptide Y receptor type 2 0.87
• Prokineticin receptor 2 0.87

Co-cited proteins · studied together in the literature

• Orexin/Hypocretin receptor type 1 4 shared papers
• Hypocretin neuropeptide precursor 2 shared papers
• Orexin receptor type 2 1 shared papers
• Hypocretin neuropeptide precursor 1 shared papers
• Orexin/Hypocretin receptor type 1 1 shared papers
• Hypocretin neuropeptide precursor 1 shared papers
• Hypocretin neuropeptide precursor 1 shared papers

Literature · 11 cited papers

• The G protein preference of orexin receptors is currently an unresolved issue. Nat. Commun. · 2023
• Reply to: The G protein preference of orexin receptors is currently an unresolved issue. Nat. Commun. · 2023
• Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor. Structure · 2022
• Molecular mechanism of the wake-promoting agent TAK-925. Nat. Commun. · 2022
• Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation. Nat. Commun. · 2021
• Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis. J. Med. Chem. · 2020
• Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors. Nat. Struct. Mol. Biol. · 2016
• Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. Nature · 2015
• The DNA sequence and analysis of human chromosome 6. Nature · 2003
• Polymorphisms in hypocretin/orexin pathway genes and narcolepsy. Neurology · 2001
• Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell · 1998