title: Structural features for functional selectivity at serotonin receptors.
abstract: Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wacker
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Meihua
authors.initials: M
authors.lastname: Chu
authors.forename: Fai Yiu
authors.initials: FY
authors.lastname: Siu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019393:Arrestin / Q000378:metabolism; D019390:Arrestins / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004873:Ergolines / Q000737:chemistry / Q000378:metabolism; D004878:Ergotamine / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008238:Lysergic Acid Diethylamide / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; 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; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019393:Arrestin; D019390:Arrestins; D004873:Ergolines; C470302:HTR1B protein, human; D008024:Ligands; D044302:Receptor, Serotonin, 5-HT1B; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D000071557:beta-Arrestins; D008238:Lysergic Acid Diethylamide; D004878:Ergotamine