ID MC3R_HUMAN Reviewed; 323 AA. AC P41968; Q4KN27; Q9H517; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 11-JUL-2012, sequence version 3. DT 27-MAR-2024, entry version 196. DE RecName: Full=Melanocortin receptor 3; DE Short=MC3-R; GN Name=MC3R; 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 [GENOMIC DNA], AND VARIANT ILE-44. RX PubMed=8463333; DOI=10.1016/s0021-9258(18)53088-x; RA Gantz I., Konda Y., Tashiro T., Shimoto Y., Miwa H., Munzert G., RA Watson S.J., Delvalle J., Yamada T.; RT "Molecular cloning of a novel melanocortin receptor."; RL J. Biol. Chem. 268:8246-8250(1993). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kopatz S.A., Aronstam R.S., Sharma S.V.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP TRANSLATIONAL START SITE. RX PubMed=22433616; DOI=10.1159/000336070; RA Tarnow P., Rediger A., Schulz A., Gruters A., Biebermann H.; RT "Identification of the translation start site of the human melanocortin 3 RT receptor."; RL Obes. Facts 5:45-51(2012). RN [6] RP VARIANT ASN-146, AND ASSOCIATION WITH SUSCEPTIBILITY TO OBESITY. RX PubMed=11889220; DOI=10.1210/jcem.87.3.8461; RA Lee Y.-S., Poh L.K.-S., Loke K.-Y.; RT "A novel melanocortin 3 receptor gene (MC3R) mutation associated with RT severe obesity."; RL J. Clin. Endocrinol. Metab. 87:1423-1426(2002). RN [7] RP CHARACTERIZATION OF VARIANTS ILE-44 AND ASN-146. RX PubMed=15292330; DOI=10.1210/jc.2004-0367; RA Tao Y.-X., Segaloff D.L.; RT "Functional characterization of melanocortin-3 receptor variants identify a RT loss-of-function mutation involving an amino acid critical for G protein- RT coupled receptor activation."; RL J. Clin. Endocrinol. Metab. 89:3936-3942(2004). RN [8] RP VARIANT SER-298, CHARACTERIZATION OF VARIANT SER-298, AND ASSOCIATION WITH RP SUSCEPTIBILITY TO OBESITY. RX PubMed=18231126; DOI=10.1038/sj.ejhg.5202005; RA Mencarelli M., Walker G.E., Maestrini S., Alberti L., Verti B., Brunani A., RA Petroni M.L., Tagliaferri M., Liuzzi A., Di Blasio A.M.; RT "Sporadic mutations in melanocortin receptor 3 in morbid obese RT individuals."; RL Eur. J. Hum. Genet. 16:581-586(2008). CC -!- FUNCTION: Receptor for MSH (alpha, beta and gamma) and ACTH. This CC receptor is mediated by G proteins which activate adenylate cyclase. CC Required for expression of anticipatory patterns of activity and CC wakefulness during periods of limited nutrient availability and for the CC normal regulation of circadian clock activity in the brain. CC {ECO:0000250|UniProtKB:P33033}. CC -!- INTERACTION: CC P41968; Q8TCY5: MRAP; NbExp=2; IntAct=EBI-9538510, EBI-9538727; CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. CC -!- TISSUE SPECIFICITY: Brain, placental, and gut tissues. CC -!- POLYMORPHISM: Genetic variations in MC3R define the body mass index CC quantitative trait locus 9 (BMIQ9) [MIM:602025]. Variance in body mass CC index is a susceptibility factor for obesity. CC {ECO:0000269|PubMed:11889220, ECO:0000269|PubMed:18231126}. CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC -!- SEQUENCE CAUTION: CC Sequence=AAC13541.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH69105.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH69599.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH96702.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH96737.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH98169.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAH98351.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAO72726.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L06155; AAC13541.1; ALT_INIT; Genomic_DNA. DR EMBL; AY227893; AAO72726.1; ALT_INIT; mRNA. DR EMBL; AL139824; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC069105; AAH69105.1; ALT_INIT; mRNA. DR EMBL; BC069599; AAH69599.1; ALT_INIT; mRNA. DR EMBL; BC096702; AAH96702.1; ALT_INIT; mRNA. DR EMBL; BC096737; AAH96737.1; ALT_INIT; mRNA. DR EMBL; BC098169; AAH98169.1; ALT_INIT; mRNA. DR EMBL; BC098351; AAH98351.1; ALT_INIT; mRNA. DR CCDS; CCDS13449.2; -. DR PIR; B46647; B46647. DR RefSeq; NP_063941.3; NM_019888.3. DR PDB; 8IOC; EM; 2.86 A; R=2-323. DR PDBsum; 8IOC; -. DR AlphaFoldDB; P41968; -. DR EMDB; EMD-35615; -. DR SMR; P41968; -. DR BioGRID; 110329; 3. DR DIP; DIP-48790N; -. DR IntAct; P41968; 3. DR MINT; P41968; -. DR STRING; 9606.ENSP00000243911; -. DR BindingDB; P41968; -. DR ChEMBL; CHEMBL4644; -. DR DrugBank; DB11653; Bremelanotide. DR DrugCentral; P41968; -. DR GuidetoPHARMACOLOGY; 284; -. DR GlyCosmos; P41968; 3 sites, No reported glycans. DR GlyGen; P41968; 3 sites. DR BioMuta; MC3R; -. DR DMDM; 395398606; -. DR PaxDb; 9606-ENSP00000243911; -. DR PeptideAtlas; P41968; -. DR Antibodypedia; 2935; 381 antibodies from 37 providers. DR DNASU; 4159; -. DR Ensembl; ENST00000243911.2; ENSP00000243911.2; ENSG00000124089.4. DR GeneID; 4159; -. DR KEGG; hsa:4159; -. DR MANE-Select; ENST00000243911.2; ENSP00000243911.2; NM_019888.3; NP_063941.3. DR UCSC; uc002xxb.2; human. DR AGR; HGNC:6931; -. DR CTD; 4159; -. DR DisGeNET; 4159; -. DR GeneCards; MC3R; -. DR HGNC; HGNC:6931; MC3R. DR HPA; ENSG00000124089; Tissue enriched (brain). DR MalaCards; MC3R; -. DR MIM; 155540; gene. DR MIM; 602025; phenotype. DR neXtProt; NX_P41968; -. DR OpenTargets; ENSG00000124089; -. DR Orphanet; 217031; NON RARE IN EUROPE: Obesity due to MC3R deficiency. DR PharmGKB; PA30675; -. DR VEuPathDB; HostDB:ENSG00000124089; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT01030000234510; -. DR HOGENOM; CLU_009579_13_0_1; -. DR InParanoid; P41968; -. DR OMA; KEIVCCC; -. DR OrthoDB; 4160596at2759; -. DR PhylomeDB; P41968; -. DR TreeFam; TF332646; -. DR PathwayCommons; P41968; -. DR Reactome; R-HSA-375276; Peptide ligand-binding receptors. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; P41968; -. DR SIGNOR; P41968; -. DR BioGRID-ORCS; 4159; 10 hits in 1138 CRISPR screens. DR GeneWiki; Melanocortin_3_receptor; -. DR GenomeRNAi; 4159; -. DR Pharos; P41968; Tchem. DR PRO; PR:P41968; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; P41968; Protein. DR Bgee; ENSG00000124089; Expressed in deltoid and 11 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0004977; F:melanocortin receptor activity; TAS:ProtInc. DR GO; GO:0004980; F:melanocyte-stimulating hormone receptor activity; IPI:BHF-UCL. DR GO; GO:0042923; F:neuropeptide binding; IMP:UniProtKB. DR GO; GO:0017046; F:peptide hormone binding; IBA:GO_Central. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB. DR GO; GO:0007187; P:G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger; TAS:ProtInc. DR GO; GO:0042309; P:homoiothermy; IEA:Ensembl. DR GO; GO:0045475; P:locomotor rhythm; IEA:Ensembl. DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; TAS:ProtInc. DR GO; GO:0008217; P:regulation of blood pressure; IEA:Ensembl. DR GO; GO:0060259; P:regulation of feeding behavior; IEA:Ensembl. DR GO; GO:0002027; P:regulation of heart rate; IEA:Ensembl. DR GO; GO:0019222; P:regulation of metabolic process; IBA:GO_Central. DR GO; GO:0055078; P:sodium ion homeostasis; IEA:Ensembl. DR CDD; cd15352; 7tmA_MC3R; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR001908; MC3-5R. DR InterPro; IPR002122; Mcort_3_rcpt. DR InterPro; IPR001671; Melcrt_ACTH_rcpt. DR PANTHER; PTHR22750; G-PROTEIN COUPLED RECEPTOR; 1. DR PANTHER; PTHR22750:SF4; MELANOCORTIN RECEPTOR 3; 1. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR00534; MCRFAMILY. DR PRINTS; PR00535; MELNOCORTINR. DR PRINTS; PR01061; MELNOCORTN3R. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. DR Genevisible; P41968; HS. PE 1: Evidence at protein level; KW 3D-structure; Biological rhythms; Cell membrane; KW G-protein coupled receptor; Glycoprotein; Lipoprotein; Membrane; Palmitate; KW Receptor; Reference proteome; Transducer; Transmembrane; KW Transmembrane helix. FT CHAIN 1..323 FT /note="Melanocortin receptor 3" FT /id="PRO_0000069718" FT TOPO_DOM 1..37 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 38..63 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 64..75 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 76..100 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 101..118 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 119..140 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 141..160 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 161..181 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 182..186 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 187..210 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 211..245 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 246..268 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 269..277 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 278..301 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 302..323 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT LIPID 315 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000255" FT CARBOHYD 2 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 16 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 28 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 44 FT /note="V -> I (have ligand binding and signaling properties FT similar to wild-type; dbSNP:rs3827103)" FT /evidence="ECO:0000269|PubMed:15292330, FT ECO:0000269|PubMed:8463333" FT /id="VAR_020070" FT VARIANT 146 FT /note="I -> N (risk factor for obesity; completely lacks FT signaling in response to agonist stimulation; coexpression FT of the wild-type and the mutant receptor shows that it does FT not exert dominant-negative activity on wild-type; FT dbSNP:rs74315393)" FT /evidence="ECO:0000269|PubMed:11889220, FT ECO:0000269|PubMed:15292330" FT /id="VAR_055000" FT VARIANT 298 FT /note="I -> S (risk factor for obesity; in vitro expression FT studies demonstrate that the mutation causes complete loss FT of function; transfected cells show diffuse cytoplasmic FT staining indicating intracellular retention of the FT receptor; dbSNP:rs121913556)" FT /evidence="ECO:0000269|PubMed:18231126" FT /id="VAR_055001" SQ SEQUENCE 323 AA; 36043 MW; 98B016FC80802A97 CRC64; MNASCCLPSV QPTLPNGSEH LQAPFFSNQS SSAFCEQVFI KPEVFLSLGI VSLLENILVI LAVVRNGNLH SPMYFFLCSL AVADMLVSVS NALETIMIAI VHSDYLTFED QFIQHMDNIF DSMICISLVA SICNLLAIAV DRYVTIFYAL RYHSIMTVRK ALTLIVAIWV CCGVCGVVFI VYSESKMVIV CLITMFFAMM LLMGTLYVHM FLFARLHVKR IAALPPADGV APQQHSCMKG AVTITILLGV FIFCWAPFFL HLVLIITCPT NPYCICYTAH FNTYLVLIMC NSVIDPLIYA FRSLELRNTF REILCGCNGM NLG //