5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology

By Yao Peng, J. McCorvy, Kasper Harpsøe, K. Lansu, Shuguang Yuan, P. Popov, L. Qu, M. Pu, T. Che, Louise F. Nikolajsen and 16 more. 2018

228 citations recorded by the source corpus.

SUMMARY Drugs frequently require interactions with multiple targets — via a process known as polypharmacology — to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin, at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, methodology): “(D) Mapping of the ergotamine selectivity determinant positions (receptor sets 1 and 2 in green and orange C spheres, respectively) identified by the sequence signature tool onto a serotonin 5-HT2C receptor structure (31).”
A practical guide to large-scale docking (2021, background): “For GPCRs, initial screening assays may differ from secondary con ﬁ rmatory assays, and showing that a molecule is active in more than one assay is often quite useful.”
An Online Resource for GPCR Structure Determination and Analysis (2019, background): “54 and data not shown)—may be masking the inherent effect of the mutation.”