S
IPR017979

GPCR, family 3, conserved site

InterPro entry
Short nameGPCR_3_CS

Description

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups
[9]
. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence
[1]
. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF)
[1, 12, 11, 10, 8]
. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice
[9]
. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs
[3]
.

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length
[7]
. Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors
[4, 2, 5, 6]
. As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

This entry represents three conserved sites found in family 3 GPCR receptor proteins. The first conserved site is centred around a highly conserved hydrophobic segment in the central part of the N-terminal extracellular region; the second conserved site is centred around a cluster of six cysteines in the C-terminal part of the extracellular domain; the third conserved site is centred around the C-terminal part of the cytoplasmic loop between the fifth and sixth transmembrane domains.

References

1.Fingerprinting G-protein-coupled receptors. Attwood TK, Findlay JB. Protein Eng. 7, 195-203, (1994). View articlePMID: 8170923

2.Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Nature 366, 575-80, (1993). View articlePMID: 8255296

3.G protein-coupled receptor deorphanizations. Civelli O, Reinscheid RK, Zhang Y, Wang Z, Fredriksson R, Schioth HB. Annu. Rev. Pharmacol. Toxicol. 53, 127-46, (2013). PMID: 23020293

4.A family of metabotropic glutamate receptors. Tanabe Y, Masu M, Ishii T, Shigemoto R, Nakanishi S. Neuron 8, 169-79, (1992). View articlePMID: 1309649

5.Coexpression of full-length gamma-aminobutyric acid(B) (GABA(B)) receptors with truncated receptors and metabotropic glutamate receptor 4 supports the GABA(B) heterodimer as the functional receptor. Sullivan R, Chateauneuf A, Coulombe N, Kolakowski LF Jr, Johnson MP, Hebert TE, Ethier N, Belley M, Metters K, Abramovitz M, O'Neill GP, Ng GY. J. Pharmacol. Exp. Ther. 293, 460-7, (2000). View articlePMID: 10773016

6.A new multigene family of putative pheromone receptors. Ryba NJ, Tirindelli R. Neuron 19, 371-9, (1997). View articlePMID: 9292726

7.Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. Brauner-Osborne H, Wellendorph P, Jensen AA. 8, 169-84, (2007). View articlePMID: 17266540

8.Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Bjarnadottir TK, Gloriam DE, Hellstrand SH, Kristiansson H, Fredriksson R, Schioth HB. Genomics 88, 263-73, (2006). View articlePMID: 16753280

9.The G protein-coupled receptor repertoires of human and mouse. Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA. Proc. Natl. Acad. Sci. U.S.A. 100, 4903-8, (2003). View articlePMID: 12679517

10.IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels. Harmar AJ, Hills RA, Rosser EM, Jones M, Buneman OP, Dunbar DR, Greenhill SD, Hale VA, Sharman JL, Bonner TI, Catterall WA, Davenport AP, Delagrange P, Dollery CT, Foord SM, Gutman GA, Laudet V, Neubig RR, Ohlstein EH, Olsen RW, Peters J, Pin JP, Ruffolo RR, Searls DB, Wright MW, Spedding M. Nucleic Acids Res. 37, D680-5, (2009). View articlePMID: 18948278

11.International Union of Pharmacology. XLVI. G protein-coupled receptor list. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. Pharmacol. Rev. 57, 279-88, (2005). View articlePMID: 15914470

12.GCRDb: a G-protein-coupled receptor database. Kolakowski LF Jr. Recept. Channels 2, 1-7, (1994). PMID: 8081729

GO terms

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