Structural features for functional selectivity at serotonin receptors

Daniel Wacker, Chong Wang, Vsevolod Katritch, Gye Won Han, Xi Ping Huang, Eyal Vardy, John D. McCorvy, Yi Jiang, Meihua Chu, Fai Yiu Siu, Wei Liu, H. Eric Xu, Vadim Cherezov, Bryan L. Roth, Raymond C. Stevens

Research output: Contribution to journalArticle

416 Scopus citations

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 b-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.

Original languageEnglish (US)
Pages (from-to)615-619
Number of pages5
JournalScience
Volume340
Issue number6132
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • General

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    Wacker, D., Wang, C., Katritch, V., Han, G. W., Huang, X. P., Vardy, E., McCorvy, J. D., Jiang, Y., Chu, M., Siu, F. Y., Liu, W., Xu, H. E., Cherezov, V., Roth, B. L., & Stevens, R. C. (2013). Structural features for functional selectivity at serotonin receptors. Science, 340(6132), 615-619. https://doi.org/10.1126/science.1232808