Structural Features for Functional Selectivity at Serotonin Receptors

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 precur...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2013-05, Vol.340 (6132), p.615-619
Main Authors: Wacker, Daniel, Wang, Chong, Katritch, Vsevolod, Han, Gye Won, Huang, Xi-Ping, Vardy, Eyal, McCorvy, John D., Jiang, Yi, Chu, Meihua, Siu, Fai Yiu, Liu, Wei, Xu, H. Eric, Cherezov, Vadim, Roth, Bryan L., Stevens, Raymond C.
Format: Article
Language:English
Subjects:
Agonists
Amino Acid Motifs
Amino Acid Sequence
Arrestin - metabolism
Arrestins - metabolism
beta-Arrestins
Binding Sites
Biochemistry
Crystal structure
Crystallography, X-Ray
Ergolines - chemistry
Ergolines - metabolism
Ergotamine - chemistry
Ergotamine - metabolism
Grants
HEK293 Cells
Humans
Hydrogen bonds
Ligands
Lysergic Acid Diethylamide
Lysergic Acid Diethylamide - chemistry
Lysergic Acid Diethylamide - metabolism
Models, Molecular
Molecular Sequence Data
Narcotics
Neurons
Obesity
Pharmacology
Protein Conformation
Protein Structure, Secondary
Receptor, Serotonin, 5-HT1B - chemistry
Receptor, Serotonin, 5-HT1B - metabolism
Receptor, Serotonin, 5-HT2B - chemistry
Receptor, Serotonin, 5-HT2B - metabolism
Receptors
Receptors, Serotonin - chemistry
Receptors, Serotonin - metabolism
Sand sheets
Serotonin
Serotonin receptors
Signal Transduction
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Description
Summary: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-HT 2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT 1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT 2B receptor bound to ERG and compared it with the 5-HT 1B /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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1232808