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Department of Energy Office of Science
GM/CA @ APS Sponsors:
National Institute of General Medical Sciences (NIGMS) and National Cancer Institute (NCI) of the National Institutes of Health (NIH)

Serotonin receptors

Figure: Artist's rendering of serotonin receptors (courtesy of R. Stevens group).

Ray Stevens group (The Scripps Research Institute) and collaborators


The group of Ray Stevens at The Scripps Research Institute and collaborators investigated the structural basis for molecular recognition and functional selectivity of serotonin receptors (Wang et al., 2013; Wacker et al., 2013). Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family, which play important roles in neurotransmission and are targets of many widely prescribed drugs including atypical anti-psychotics, anti-migraine medications, anxiolytics and anti-depressants, and the recently approved anti-obesity medication lorcaserin. However, off-target interactions have resulted in serious side effects exemplified by "Fen-Phen" which has been withdrawn from the market. The researchers recently determined the structures of the human 5-HT1B receptor and 5-HT2B receptor bound to the agonist anti-migraine medications ergotamine (ERG), as well as the 5-HT1B receptor bound to dihydroergotamine. They also conducted biochemical studies that showed that the hallucinogen lysergic acid diethylamide (LSD), its precursor ERG, and related ergolines display strong functional selectivity for beta-arrestin signaling at the 5-HT2B receptor, while being relatively unbiased at the 5-HT1B receptor. Comparison of the two structures, both bound to ERG, provide insights on the structural basis for biased signaling. Given the relatively poor understanding of GPCR structure-function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.



[1] Wang, C, Jiang, Y, Ma, J, Wu, H, Wacker, D, Katritch, V, Han, GW, Liu, W, Huang, XP, Vardy, E, McCorvy, JD, Gao, X, Zhou, XE, Melcher, K, Zhang, C, Bai, F, Yang, H, Yang, L, Jiang, H, Roth, BL, Cherezov, V, Stevens, RC, Xu, HE. Structural basis for molecular recognition at serotonin receptors, Science 340, 610-614 (2013)
[2] Wacker, D, Wang, C, Katritch, V, Han, GW, Huang, XP, Vardy, E, McCorvy, JD, Jiang, Y, Chu, M, Siu, FY, Liu, W, Xu, HE, Cherezov, V, Roth, BL, Stevens, RC. Structural features for functional selectivity at serotonin receptors, Science 340, 615-619 (2013)

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