Hypocretin (orexin) receptor 2

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Orexin receptor type 2
Identifiers
Symbol	Orexin_rec2
Pfam	PF03827
InterPro	IPR004060
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

HCRTR2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4S0V
Identifiers
Aliases	HCRTR2, OX2R, Hypocretin (orexin) receptor 2, hypocretin receptor 2
External IDs	OMIM: 602393 MGI: 2680765 HomoloGene: 1168 GeneCards: HCRTR2
Gene location (Human)
Chr.	Chromosome 6 (human)[1]
End	55,282,620 bp[1]
Gene location (Mouse)
Chr.	Chromosome 9 (mouse)[2]
End	76,323,856 bp[2]
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• peptide hormone binding; • peptide binding; • G-protein coupled receptor activity; • signal transducer activity; • neuropeptide receptor activity; • orexin receptor activity;
Cellular component	• integral component of membrane; • cell membrane; • membrane; • integral component of plasma membrane;
Biological process	• phospholipase C-activating G-protein coupled receptor signaling pathway; • cellular response to hormone stimulus; • regulation of circadian sleep/wake cycle, sleep; • circadian sleep/wake cycle process; • signal transduction; • response to peptide; • chemical synaptic transmission; • regulation of cytosolic calcium ion concentration; • regulation of circadian sleep/wake cycle, wakefulness; • neuropeptide signaling pathway; • feeding behavior; • G-protein coupled receptor signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	3062
	387285
	ENSG00000137252
	ENSMUSG00000032360
	O43614
	P58308
	NM_001526
	NM_198962; NM_001364551
	NP_001517
	NP_945200; NP_001351480
	Wikidata
View/Edit Human	View/Edit Mouse

Orexin receptor type 2 (Ox2R or OX₂), also known as hypocretin receptor type 2 (HcrtR2), is a protein that in humans is encoded by the HCRTR2 gene.[5]

Structure

The structure of the receptor has been solved to 2.5 Å resolution as a fusion protein bound to suvorexant using lipid-mediated crystallization.[6]

Function

OX₂ is a G-protein coupled receptor expressed exclusively in the brain. It has 64% identity with OX₁. OX₂ binds both orexin A and orexin B neuropeptides. OX₂ is involved in the central feedback mechanism that regulates feeding behaviour.[5] Mice with enhanced OX₂ signaling are resistant to high-fat diet-induced obesity. [7]

Ligands

Agonists

Orexin-A
Orexin-B
SB-668,875

Antagonists

Almorexant - Dual OX₁ and OX₂ antagonist
EMPA - Selective OX₂ antagonist
Filorexant - Dual OX₁ and OX₂ antagonist
JNJ-10397049 (600x selective for OX₂ over OX₁)[8]
Lemborexant - Dual OX₁ and OX₂ antagonist
MIN-202 - Selective OX₂ antagonist
MK-1064 - Selective OX₂ antagonist[9]
MK-8133 - Selective OX₂ antagonist[10]
Nemorexant - Dual OX₁ and OX₂ antagonist
SB-649,868 - Dual OX₁ and OX₂ antagonist
Suvorexant - Dual OX₁ and OX₂ antagonist
TCS-OX2-29 - Selective OX₂ antagonist
(3,4-dimethoxyphenoxy)alkylamino acetamides[11]
Compound 1m - Selective OX₂ antagonist [12]

References

GRCh38: Ensembl release 89: ENSG00000137252 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000032360 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2".
Liszewski, Kathy (1 October 2015). "Dissecting the Structure of Membrane Proteins". Genetic Engineering & Biotechnology News. 35 (17): 16. doi:10.1089/gen.35.07.09.
Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, Yanagisawa M (January 2009). "Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity". Cell Metabolism. 9 (1): 64–76. doi:10.1016/j.cmet.2008.10.010. PMC 2630400. PMID 19117547.
McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, Dvorak CA, Lovenberg TW, Carruthers NI, Jones TK (Aug 2004). "Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists". Bioorganic & Medicinal Chemistry Letters. 14 (16): 4225–9. doi:10.1016/j.bmcl.2004.06.032. PMID 15261275.
Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, Lemaire W, Bruno JG, Harrell CM, Garson SL, Gotter AL, Fox SV, Stevens J, Tannenbaum PL, Prueksaritanont T, Cabalu TD, Cui D, Stellabott J, Hartman GD, Young SD, Winrow CJ, Renger JJ, Coleman PJ (Feb 2014). "Discovery of 5-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia". ChemMedChem. 9 (2): 311–22. doi:10.1002/cmdc.201300447. PMID 24376006. S2CID 26114114.
Kuduk SD, Skudlarek JW, DiMarco CN, Bruno JG, Pausch MH, O'Brien JA, Cabalu TD, Stevens J, Brunner J, Tannenbaum PL, Garson SL, Savitz AT, Harrell CM, Gotter AL, Winrow CJ, Renger JJ, Coleman PJ (Jun 2015). "Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties". Bioorganic & Medicinal Chemistry Letters. 25 (12): 2488–92. doi:10.1016/j.bmcl.2015.04.066. PMID 25981685.
Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, Waksmunski FS, Strohl B, Tellew JE, Williams JP, Saunders J, Appell KC, Henderson I, Webb ML (Oct 2008). "Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 18 (20): 5420–3. doi:10.1016/j.bmcl.2008.09.038. PMID 18815029.
Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, Yoshikubo S, Hirai K, Marui S (Nov 2011). "Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 21 (21): 6414–6. doi:10.1016/j.bmcl.2011.08.093. PMID 21917455.

Flier JS, Maratos-Flier E (Feb 1998). "Obesity and the hypothalamus: novel peptides for new pathways". Cell. 92 (4): 437–40. doi:10.1016/S0092-8674(00)80937-X. PMID 9491885. S2CID 14768585.
Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001). "To eat or to sleep? Orexin in the regulation of feeding and wakefulness". Annual Review of Neuroscience. 24: 429–58. doi:10.1146/annurev.neuro.24.1.429. PMID 11283317.
Hungs M, Mignot E (May 2001). "Hypocretin/orexin, sleep and narcolepsy". BioEssays. 23 (5): 397–408. doi:10.1002/bies.1058. PMID 11340621. S2CID 541650.
de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (Jan 1998). "The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity". Proceedings of the National Academy of Sciences of the United States of America. 95 (1): 322–7. Bibcode:1998PNAS...95..322D. doi:10.1073/pnas.95.1.322. PMC 18213. PMID 9419374.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (Feb 1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior" (PDF). Cell. 92 (4): 573–85. doi:10.1016/S0092-8674(00)80949-6. PMID 9491897. S2CID 16294729.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (Mar 1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior". Cell. 92 (5): 1 page following 696. doi:10.1016/S0092-8674(02)09256-5. PMID 9527442.
Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E (Sep 2000). "A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains". Nature Medicine. 6 (9): 991–7. doi:10.1038/79690. PMID 10973318. S2CID 18076282.
Wright GJ, Puklavec MJ, Willis AC, Hoek RM, Sedgwick JD, Brown MH, Barclay AN (Aug 2000). "Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function". Immunity. 13 (2): 233–42. doi:10.1016/S1074-7613(00)00023-6. PMID 10981966.
Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG (Feb 2001). "Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade". The Journal of Clinical Endocrinology and Metabolism. 86 (2): 778–82. doi:10.1210/jc.86.2.778. PMID 11158046.
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Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW (Sep 2001). "Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals". The Journal of Clinical Endocrinology and Metabolism. 86 (9): 4512–9. doi:10.1210/jc.86.9.4512. PMID 11549701.
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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000137252 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000032360 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2".

[6] Liszewski, Kathy (1 October 2015). "Dissecting the Structure of Membrane Proteins". Genetic Engineering & Biotechnology News. 35 (17): 16. doi:10.1089/gen.35.07.09.

[pmid19117547-7] Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, Yanagisawa M (January 2009). "Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity". Cell Metabolism. 9 (1): 64–76. doi:10.1016/j.cmet.2008.10.010. PMC 2630400. PMID 19117547.

[pmid15261275-8] McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, Dvorak CA, Lovenberg TW, Carruthers NI, Jones TK (Aug 2004). "Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists". Bioorganic & Medicinal Chemistry Letters. 14 (16): 4225–9. doi:10.1016/j.bmcl.2004.06.032. PMID 15261275.

[pmid24376006-9] Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, Lemaire W, Bruno JG, Harrell CM, Garson SL, Gotter AL, Fox SV, Stevens J, Tannenbaum PL, Prueksaritanont T, Cabalu TD, Cui D, Stellabott J, Hartman GD, Young SD, Winrow CJ, Renger JJ, Coleman PJ (Feb 2014). "Discovery of 5-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia". ChemMedChem. 9 (2): 311–22. doi:10.1002/cmdc.201300447. PMID 24376006. S2CID 26114114.

[pmid25981685-10] Kuduk SD, Skudlarek JW, DiMarco CN, Bruno JG, Pausch MH, O'Brien JA, Cabalu TD, Stevens J, Brunner J, Tannenbaum PL, Garson SL, Savitz AT, Harrell CM, Gotter AL, Winrow CJ, Renger JJ, Coleman PJ (Jun 2015). "Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties". Bioorganic & Medicinal Chemistry Letters. 25 (12): 2488–92. doi:10.1016/j.bmcl.2015.04.066. PMID 25981685.

[pmid18815029-11] Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, Waksmunski FS, Strohl B, Tellew JE, Williams JP, Saunders J, Appell KC, Henderson I, Webb ML (Oct 2008). "Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 18 (20): 5420–3. doi:10.1016/j.bmcl.2008.09.038. PMID 18815029.

[PMID_21917455-12] Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, Yoshikubo S, Hirai K, Marui S (Nov 2011). "Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 21 (21): 6414–6. doi:10.1016/j.bmcl.2011.08.093. PMID 21917455.