Hypocretin (orexin) receptor 2

Last updated

HCRTR2
HCRTR2.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HCRTR2 , OX2R, Hypocretin (orexin) receptor 2, hypocretin receptor 2, ORXR2, OXR2
External IDs OMIM: 602393; MGI: 2680765; HomoloGene: 1168; GeneCards: HCRTR2; OMA:HCRTR2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001526
NM_001384272

NM_198962
NM_001364551

RefSeq (protein)

NP_001517

NP_945200
NP_001351480

Location (UCSC) Chr 6: 55.11 – 55.28 Mb Chr 9: 76.13 – 76.23 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Orexin receptor type 2
Identifiers
SymbolOrexin_rec2
Pfam PF03827
InterPro IPR004060
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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] It should not be confused for the protein CD200R1 which shares the alias OX2R but is a distinct, unrelated gene located on the human chromosome 3. [6]

Contents

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. [7]

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. [8]

This receptor is activated by Hipocretin, which is a wake-promoting hypothalamic neuropeptide that acts as a critical regulator of sleep in animals as Zebrafish or Mammals. This protein has mutations in Astyanax mexicanus that reduces the sleep needs of the cavefish. [9]

Ligands

Agonists

Antagonists

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137252 Ensembl, May 2017
  2. 1 2 3 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.
  5. 1 2 "Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2".
  6. "Genecards CD200R1" . Retrieved 2024-07-17.
  7. Liszewski K (1 October 2015). "Dissecting the Structure of Membrane Proteins" . Genetic Engineering & Biotechnology News . 35 (17): 16. doi:10.1089/gen.35.07.09.
  8. Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, et al. (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.
  9. Warren WC, Boggs TE, Borowsky R, Carlson BM, Ferrufino E, Gross JB, et al. (March 2021). "A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution". Nature Communications. 12 (1): 1447. Bibcode:2021NatCo..12.1447W. doi:10.1038/s41467-021-21733-z. PMC   7933363 . PMID   33664263.
  10. 1 2 "WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 263 : International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). Who.int. Retrieved 2021-11-30.
  11. 1 2 WOapplication 2019027058,Kajita, Yuichi; Mikami, Satoshi& Miyanohana, Yuheiet al.,"Heterocyclic compound and use therof",published 2019-02-07, assigned to Takeda Pharmaceutical Company
  12. 1 2 Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, et al. (September 1999). "Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR". British Journal of Pharmacology. 128 (1): 1–3. doi:10.1038/sj.bjp.0702780. PMC   1571615 . PMID   10498827.
  13. 1 2 Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ (January 2004). "Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor". British Journal of Pharmacology. 141 (2): 340–346. doi:10.1038/sj.bjp.0705610. PMC   1574197 . PMID   14691055.
  14. "Wave 1 Pipeline Market Opportunity Conference Call" (PDF). Takeda Pharmaceutical Company Limited. 8 December 2020. Archived from the original (PDF) on 2021-10-20. TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20
  15. McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, et al. (August 2004). "Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists". Bioorganic & Medicinal Chemistry Letters. 14 (16): 4225–4229. doi:10.1016/j.bmcl.2004.06.032. PMID   15261275.
  16. Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, et al. (February 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): 311–322. doi:10.1002/cmdc.201300447. PMID   24376006. S2CID   26114114.
  17. Kuduk SD, Skudlarek JW, DiMarco CN, Bruno JG, Pausch MH, O'Brien JA, et al. (June 2015). "Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties". Bioorganic & Medicinal Chemistry Letters. 25 (12): 2488–2492. doi:10.1016/j.bmcl.2015.04.066. PMID   25981685.
  18. Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, et al. (October 2008). "Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 18 (20): 5420–5423. doi:10.1016/j.bmcl.2008.09.038. PMID   18815029.
  19. Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, et al. (November 2011). "Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists". Bioorganic & Medicinal Chemistry Letters. 21 (21): 6414–6416. doi:10.1016/j.bmcl.2011.08.093. PMID   21917455.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.