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Science 340 (6132): 615-619

Copyright © 2013 by the American Association for the Advancement of Science

Structural Features for Functional Selectivity at Serotonin Receptors

Daniel Wacker,1 Chong Wang,1 Vsevolod Katritch,1 Gye Won Han,1 Xi-Ping Huang,2 Eyal Vardy,2 John D. McCorvy,2 Yi Jiang,1,3 Meihua Chu,1 Fai Yiu Siu,1 Wei Liu,1 H. Eric Xu,3,4 Vadim Cherezov,1 Bryan L. Roth,2,* Raymond C. Stevens1,*

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.

1 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27599, USA.
3 Van Andel Research Institute/Shanghai Institute of Materia Medica Center, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
4 Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA.

* Corresponding author. E-mail: bryan_roth{at} (B.L.R.); stevens{at} (R.C.S.)

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