Structural Features for Functional Selectivity at Serotonin Receptors

By Daniel Wacker, Chong Wang, Vsevolod Katritch, G. Han, Xi Ping Huang, E. Vardy, J. McCorvy, Yi Jiang, M. Chu, F. Siu and 5 more. Science, 2013

685 citations recorded by the source corpus.

Dissecting Serotonin Receptors Serotonin receptors are the targets for many widely used drugs prescribed to treat ailments from depression to obesity and migraine headaches (see the Perspective by Palczewski and Kiser). C. Wang et al. (p. 610, published online 21 March) and Wacker et al. (p. 615, published online 21 March) describe crystal structures of two members of the serotonin family of receptors bound to antimigraine medications or to a precursor of the hallucinogenic drug LSD. Subtle differences in the way particular ligands bind to the receptors cause substantial differences in the signals generated by the receptor and the consequent biological responses. The structures reveal how the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which particular receptor it binds. Structures of serotonin receptor family members in complex with the fungal alkaloid ergot offer clues for drug designers. [Also see Perspective by Palczewski and Kiser] 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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/87b44f07854cb79e5babfabed9487eced1600a97

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Citations in the corpus

5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology (2018, methodology): “Superposition of the 5-HT1B, 2B, 2C-ERG and 5-HT2C-RIT (Wacker et al., 2013; Wang et al., 2013) structures shows an increased opening on the intracellular ends of helices V and VI in the order 5-HT2B-ERG < 5-HT1B-ERG < 5-HT2C-ERG compared to 5-HT2C-RIT (Figures 1C and S2).”
Pharmacogenomics of GPCR Drug Targets (2018, neutral): “, 2014), micro-switches that are critical for receptor conformational changes (Trzaskowski et al., 2012; Venkatakrishnan et al., 2016; Wacker et al., 2013), as well as post-translational modification sites such as N-glycosylation in the N-terminal tail and phosphorylation in the C-terminal tail that”
Multiple conformational states in retrospective virtual screening – homology models vs. crystal structures: beta-2 adrenergic receptor case study (2015, neutral): “5-HT2BR 4IB4 [24] 2.”
DREADDs for Neuroscientists (2016, background): “…et al., 2013), pharmacological (Weiss et al., 2013; Fenalti et al., 2014), and structural evidence (Fenalti et al., 2014; Manglik et al., 2015; Rasmussen et al., 2011; Wacker et al., 2013)—is crucial for understanding how GPCR-based chemogenetic technologies can be harnessed in neuroscience.”
Serotonin syndrome. (2014, background): “2011) despite intensive research in this area (Wang et al. 2013; Wacker et al. 2013).”
PRESTO-TANGO: an open-source resource for interrogation of the druggable human GPCR-ome (2015, positive): “…used by many others, including us, for the DRD2 dopamine receptor 38 , the δ -opiod 39 and κ -opiod 40,41 receptors and several serotonin receptors 42 , the present study is, to our knowledge, the first to adapt it to almost the entire nonolfactory GPCRome and to make the entire resource publicly…”