OX2R_HUMAN
ID OX2R_HUMAN Reviewed; 444 AA.
AC O43614; Q5VTM0;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 23-SEP-2008, sequence version 2.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Orexin receptor type 2;
DE Short=Ox-2-R;
DE Short=Ox2-R;
DE Short=Ox2R;
DE AltName: Full=Hypocretin receptor type 2;
GN Name=HCRTR2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND VARIANT
RP VAL-308.
RX PubMed=9491897; DOI=10.1016/s0092-8674(00)80949-6;
RA Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli R.M., Tanaka H.,
RA Williams S.C., Richardson J.A., Kozlowski G.P., Wilson S., Arch J.R.S.,
RA Buckingham R.E., Haynes A.C., Carr S.A., Annan R.S., McNulty D.E.,
RA Liu W.-S., Terrett J.A., Elshourbagy N.A., Bergsma D.J., Yanagisawa M.;
RT "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G
RT protein-coupled receptors that regulate feeding behavior.";
RL Cell 92:573-585(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-10; THR-11; VAL-293 AND
RP VAL-308.
RX PubMed=11723285; DOI=10.1212/wnl.57.10.1896;
RA Olafsdottir B.R., Rye D.B., Scammell T.E., Matheson J.K., Stefansson K.,
RA Gulcher J.R.;
RT "Polymorphisms in hypocretin/orexin pathway genes and narcolepsy.";
RL Neurology 57:1896-1899(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP REVIEW.
RX PubMed=11340621; DOI=10.1002/bies.1058;
RA Hungs M., Mignot E.;
RT "Hypocretin/orexin, sleep and narcolepsy.";
RL Bioessays 23:397-408(2001).
RN [6]
RP REVIEW.
RX PubMed=11283317; DOI=10.1146/annurev.neuro.24.1.429;
RA Willie J.T., Chemelli R.M., Sinton C.M., Yanagisawa M.;
RT "To eat or to sleep? Orexin in the regulation of feeding and wakefulness.";
RL Annu. Rev. Neurosci. 24:429-458(2001).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY, MUTAGENESIS OF 33-ASP--HIS-49;
RP TRP-44 AND ASN-324, AND DOMAIN.
RX PubMed=26950369; DOI=10.1038/nsmb.3183;
RA Yin J., Babaoglu K., Brautigam C.A., Clark L., Shao Z., Scheuermann T.H.,
RA Harrell C.M., Gotter A.L., Roecker A.J., Winrow C.J., Renger J.J.,
RA Coleman P.J., Rosenbaum D.M.;
RT "Structure and ligand-binding mechanism of the human OX1 and OX2 orexin
RT receptors.";
RL Nat. Struct. Mol. Biol. 23:293-299(2016).
RN [8] {ECO:0007744|PDB:4S0V}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 3-254 AND 294-388 IN COMPLEX WITH
RP THE INHIBITOR SUVOREXANT, TOPOLOGY, SUBCELLULAR LOCATION, AND DISULFIDE
RP BONDS.
RX PubMed=25533960; DOI=10.1038/nature14035;
RA Yin J., Mobarec J.C., Kolb P., Rosenbaum D.M.;
RT "Crystal structure of the human OX2 orexin receptor bound to the insomnia
RT drug suvorexant.";
RL Nature 519:247-250(2015).
CC -!- FUNCTION: Nonselective, high-affinity receptor for both orexin-A and
CC orexin-B neuropeptides (PubMed:9491897, PubMed:26950369). Triggers an
CC increase in cytoplasmic Ca(2+) levels in response to orexin-A binding
CC (PubMed:9491897, PubMed:26950369). {ECO:0000269|PubMed:26950369,
CC ECO:0000269|PubMed:9491897}.
CC -!- INTERACTION:
CC O43614; P62937: PPIA; NbExp=3; IntAct=EBI-25884102, EBI-437708;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26950369,
CC ECO:0000269|PubMed:9491897, ECO:0000305|PubMed:25533960}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:25533960}.
CC -!- DOMAIN: The N-terminal region is required for orexin signaling.
CC {ECO:0000269|PubMed:26950369}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; AF041245; AAC39602.1; -; mRNA.
DR EMBL; AY062031; AAL47215.1; -; Genomic_DNA.
DR EMBL; AL591718; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL449104; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471081; EAX04440.1; -; Genomic_DNA.
DR CCDS; CCDS4956.1; -.
DR RefSeq; NP_001517.2; NM_001526.4.
DR PDB; 4S0V; X-ray; 2.50 A; A=3-254, A=294-388.
DR PDB; 5WQC; X-ray; 1.96 A; A=3-254, A=294-386.
DR PDB; 5WS3; X-ray; 2.30 A; A=3-254, A=294-388.
DR PDB; 6TPG; X-ray; 2.74 A; A=1-254, A=294-307.
DR PDB; 6TPJ; X-ray; 2.74 A; A/B=1-254, A/B=294-307.
DR PDB; 6TPN; X-ray; 2.61 A; A=1-254, A=294-388.
DR PDB; 7L1U; EM; 3.20 A; R=3-389.
DR PDB; 7L1V; EM; 3.00 A; R=3-389.
DR PDBsum; 4S0V; -.
DR PDBsum; 5WQC; -.
DR PDBsum; 5WS3; -.
DR PDBsum; 6TPG; -.
DR PDBsum; 6TPJ; -.
DR PDBsum; 6TPN; -.
DR PDBsum; 7L1U; -.
DR PDBsum; 7L1V; -.
DR AlphaFoldDB; O43614; -.
DR SMR; O43614; -.
DR BioGRID; 109312; 35.
DR IntAct; O43614; 1.
DR STRING; 9606.ENSP00000477548; -.
DR BindingDB; O43614; -.
DR ChEMBL; CHEMBL4792; -.
DR DrugBank; DB11951; Lemborexant.
DR DrugBank; DB09034; Suvorexant.
DR DrugCentral; O43614; -.
DR GuidetoPHARMACOLOGY; 322; -.
DR GlyGen; O43614; 3 sites.
DR iPTMnet; O43614; -.
DR PhosphoSitePlus; O43614; -.
DR BioMuta; HCRTR2; -.
DR EPD; O43614; -.
DR MassIVE; O43614; -.
DR PaxDb; O43614; -.
DR PeptideAtlas; O43614; -.
DR PRIDE; O43614; -.
DR Antibodypedia; 17332; 369 antibodies from 38 providers.
DR DNASU; 3062; -.
DR Ensembl; ENST00000370862.4; ENSP00000359899.3; ENSG00000137252.10.
DR Ensembl; ENST00000615358.4; ENSP00000477548.1; ENSG00000137252.10.
DR GeneID; 3062; -.
DR KEGG; hsa:3062; -.
DR MANE-Select; ENST00000370862.4; ENSP00000359899.3; NM_001384272.1; NP_001371201.1.
DR CTD; 3062; -.
DR DisGeNET; 3062; -.
DR GeneCards; HCRTR2; -.
DR HGNC; HGNC:4849; HCRTR2.
DR HPA; ENSG00000137252; Tissue enriched (brain).
DR MIM; 602393; gene.
DR neXtProt; NX_O43614; -.
DR OpenTargets; ENSG00000137252; -.
DR PharmGKB; PA29223; -.
DR VEuPathDB; HostDB:ENSG00000137252; -.
DR eggNOG; KOG3656; Eukaryota.
DR GeneTree; ENSGT01020000230390; -.
DR HOGENOM; CLU_009579_6_3_1; -.
DR InParanoid; O43614; -.
DR OMA; AEVYPKM; -.
DR OrthoDB; 981089at2759; -.
DR PhylomeDB; O43614; -.
DR TreeFam; TF315303; -.
DR PathwayCommons; O43614; -.
DR Reactome; R-HSA-389397; Orexin and neuropeptides FF and QRFP bind to their respective receptors.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR SignaLink; O43614; -.
DR SIGNOR; O43614; -.
DR BioGRID-ORCS; 3062; 14 hits in 1060 CRISPR screens.
DR ChiTaRS; HCRTR2; human.
DR GeneWiki; Hypocretin_(orexin)_receptor_2; -.
DR GenomeRNAi; 3062; -.
DR Pharos; O43614; Tclin.
DR PRO; PR:O43614; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; O43614; protein.
DR Bgee; ENSG00000137252; Expressed in cortical plate and 37 other tissues.
DR ExpressionAtlas; O43614; baseline and differential.
DR Genevisible; O43614; HS.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0004930; F:G protein-coupled receptor activity; IBA:GO_Central.
DR GO; GO:0008188; F:neuropeptide receptor activity; TAS:ProtInc.
DR GO; GO:0016499; F:orexin receptor activity; IDA:UniProtKB.
DR GO; GO:0017046; F:peptide hormone binding; IEA:Ensembl.
DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc.
DR GO; GO:0022410; P:circadian sleep/wake cycle process; IEA:InterPro.
DR GO; GO:0007631; P:feeding behavior; TAS:ProtInc.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0040011; P:locomotion; IEA:Ensembl.
DR GO; GO:0007218; P:neuropeptide signaling pathway; IDA:UniProtKB.
DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0010840; P:regulation of circadian sleep/wake cycle, wakefulness; ISS:UniProtKB.
DR GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; IDA:UniProtKB.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR000204; Orexin_rcpt.
DR InterPro; IPR004060; Orexin_rcpt_2.
DR Pfam; PF00001; 7tm_1; 1.
DR Pfam; PF03827; Orexin_rec2; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01522; OREXIN2R.
DR PRINTS; PR01064; OREXINR.
DR SMART; SM01381; 7TM_GPCR_Srsx; 1.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Disulfide bond; G-protein coupled receptor;
KW Glycoprotein; Membrane; Receptor; Reference proteome; Transducer;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..444
FT /note="Orexin receptor type 2"
FT /id="PRO_0000069989"
FT TOPO_DOM 1..54
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:25533960,
FT ECO:0000305|PubMed:26950369"
FT TRANSMEM 55..75
FT /note="Helical; Name=1"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TOPO_DOM 76..88
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TRANSMEM 89..110
FT /note="Helical; Name=2"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TOPO_DOM 111..127
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TRANSMEM 128..150
FT /note="Helical; Name=3"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TOPO_DOM 151..170
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TRANSMEM 171..191
FT /note="Helical; Name=4"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TOPO_DOM 192..222
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TRANSMEM 223..243
FT /note="Helical; Name=5"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TOPO_DOM 244..304
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TRANSMEM 305..326
FT /note="Helical; Name=6"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TOPO_DOM 327..342
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TRANSMEM 343..366
FT /note="Helical; Name=7"
FT /evidence="ECO:0000269|PubMed:25533960"
FT TOPO_DOM 367..444
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:25533960"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 33..49
FT /note="Required for response to orexin-A"
FT /evidence="ECO:0000269|PubMed:26950369"
FT BINDING 324
FT /ligand="suvorexant"
FT /ligand_id="ChEBI:CHEBI:82698"
FT /ligand_note="antagonist"
FT /evidence="ECO:0000269|PubMed:25533960,
FT ECO:0007744|PDB:4S0V"
FT SITE 44
FT /note="Important for responses to orexin"
FT /evidence="ECO:0000269|PubMed:26950369"
FT CARBOHYD 14
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 22
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 202
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 127..210
FT /evidence="ECO:0007744|PDB:4S0V"
FT VARIANT 10
FT /note="P -> S (in dbSNP:rs41271310)"
FT /evidence="ECO:0000269|PubMed:11723285"
FT /id="VAR_044507"
FT VARIANT 11
FT /note="P -> T (in dbSNP:rs41271312)"
FT /evidence="ECO:0000269|PubMed:11723285"
FT /id="VAR_044508"
FT VARIANT 293
FT /note="I -> V (in dbSNP:rs74720027)"
FT /evidence="ECO:0000269|PubMed:11723285"
FT /id="VAR_044509"
FT VARIANT 308
FT /note="I -> V (in dbSNP:rs2653349)"
FT /evidence="ECO:0000269|PubMed:11723285,
FT ECO:0000269|PubMed:9491897"
FT /id="VAR_044510"
FT MUTAGEN 33..49
FT /note="Missing: Abolishes response to orexin-A."
FT /evidence="ECO:0000269|PubMed:26950369"
FT MUTAGEN 44
FT /note="W->N: Abolishes response to orexin-A."
FT /evidence="ECO:0000269|PubMed:26950369"
FT MUTAGEN 324
FT /note="N->A: Strongly impairs response to orexin-A."
FT /evidence="ECO:0000269|PubMed:26950369"
FT HELIX 40..47
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 54..81
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 88..106
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 108..117
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 123..156
FT /evidence="ECO:0007829|PDB:5WQC"
FT STRAND 158..160
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 166..183
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 185..190
FT /evidence="ECO:0007829|PDB:5WQC"
FT STRAND 191..196
FT /evidence="ECO:0007829|PDB:5WQC"
FT STRAND 199..202
FT /evidence="ECO:0007829|PDB:5WS3"
FT STRAND 207..212
FT /evidence="ECO:0007829|PDB:5WQC"
FT STRAND 215..217
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 218..231
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 233..251
FT /evidence="ECO:0007829|PDB:5WQC"
FT TURN 252..254
FT /evidence="ECO:0007829|PDB:6TPN"
FT HELIX 294..328
FT /evidence="ECO:0007829|PDB:5WQC"
FT TURN 332..335
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 339..367
FT /evidence="ECO:0007829|PDB:5WQC"
FT HELIX 369..381
FT /evidence="ECO:0007829|PDB:5WQC"
SQ SEQUENCE 444 AA; 50694 MW; C4C9A153D42254C6 CRC64;
MSGTKLEDSP PCRNWSSASE LNETQEPFLN PTDYDDEEFL RYLWREYLHP KEYEWVLIAG
YIIVFVVALI GNVLVCVAVW KNHHMRTVTN YFIVNLSLAD VLVTITCLPA TLVVDITETW
FFGQSLCKVI PYLQTVSVSV SVLTLSCIAL DRWYAICHPL MFKSTAKRAR NSIVIIWIVS
CIIMIPQAIV MECSTVFPGL ANKTTLFTVC DERWGGEIYP KMYHICFFLV TYMAPLCLMV
LAYLQIFRKL WCRQIPGTSS VVQRKWKPLQ PVSQPRGPGQ PTKSRMSAVA AEIKQIRARR
KTARMLMIVL LVFAICYLPI SILNVLKRVF GMFAHTEDRE TVYAWFTFSH WLVYANSAAN
PIIYNFLSGK FREEFKAAFS CCCLGVHHRQ EDRLTRGRTS TESRKSLTTQ ISNFDNISKL
SEQVVLTSIS TLPAANGAGP LQNW
