Journal
SCIENCE
Volume 340, Issue 6132, Pages 615-619Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1232808
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Funding
- National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative [U54 GM094618]
- NIH [P50 GM073197]
- Jay and Betty Van Andel Foundation, Amway (China) [R01 DK071662]
- Ministry of Science and Technology (China) [2012ZX09301001-005, 2012CB910403, U19 MH82441, R01 MH61887]
- National Institute of Mental Health Psychoactive Drug Screening Program
- Michael Hooker Chair of Pharmacology
- Boehringer Ingelheim Fonds Ph.D. Fellowship
- Receptos
- GPCR structure-based drug discovery company
- National Cancer Institute [Y1-CO-1020]
- NIGMS [Y1-GM-1104]
- Office of Science of the U.S. Department of Energy
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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 beta-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.
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