title: Structure and function of serotonin G protein-coupled receptors.
abstract: Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for disorders ranging from migraine headaches to neuropsychiatric disorders such as schizophrenia and depression. There are 14 distinct serotonin receptors, of which 13 are G protein-coupled receptors (GPCRs), which are targets for approximately 40% of the approved medicines. Recent crystallographic and biochemical evidence has provided a converging understanding of the basic structure and functional mechanics of GPCR activation. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptor, with the antimigraine and valvulopathic drug ergotamine bound. The first serotonin crystal structures not only provide the first evidence of serotonin receptor topography but also provide mechanistic explanations into functional selectivity or biased agonism. This review will detail the findings of these crystal structures from a molecular and mutagenesis perspective for driving rational drug design for novel therapeutics incorporating biased signaling.
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.affiliation: Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27514, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D000495:Allosteric Site; D000818:Animals; D004878:Ergotamine / Q000494:pharmacology / Q000627:therapeutic use; D019204:GTP-Binding Proteins / Q000502:physiology; D006349:Heart Valve Diseases / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D044302:Receptor, Serotonin, 5-HT1B / Q000737:chemistry / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry / Q000378:metabolism; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D014662:Vasoconstrictor Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D044302:Receptor, Serotonin, 5-HT1B; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D019204:GTP-Binding Proteins; D004878:Ergotamine
keywords: 5-HT(1B); 5-HT(2B); Functional selectivity; GPCR; Serotonin; β-Arrestin