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

Yao Peng | Zendy; John D. McCorvy | Zendy; Kasper Harpsøe | Zendy; Katherine Lansu | Zendy; Shuguang Yuan | Zendy; Petr Popov | Zendy; Lu Qu | Zendy; Mengchen Pu | Zendy; Tao Che | Zendy; Louise F. Nikolajsen | Zendy; XiPing Huang | Zendy; Yiran Wu | Zendy; Ling Shen | Zendy; Walden E. BjørnYoshimoto | Zendy; Kang Ding | Zendy; Daniel Wacker | Zendy; Gye Won Han | Zendy; Jianjun Cheng | Zendy; Vsevolod Katritch | Zendy; Anders A. Jensen | Zendy; Michael A. Hanson | Zendy; Suwen Zhao | Zendy; David E. Gloriam | Zendy; Bryan L. Roth | Zendy; Raymond C. Stevens | Zendy; ZhiJie Liu | Zendy

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

Author(s) -

Yao Peng,

John D. McCorvy,

Kasper Harpsøe,

Katherine Lansu,

Shuguang Yuan,

Petr Popov,

Lu Qu,

Mengchen Pu,

Tao Che,

Louise F. Nikolajsen,

XiPing Huang,

Yiran Wu,

Ling Shen,

Walden E. BjørnYoshimoto,

Kang Ding,

Daniel Wacker,

Gye Won Han,

Jianjun Cheng,

Vsevolod Katritch,

Anders A. Jensen,

Michael A. Hanson,

Suwen Zhao,

David E. Gloriam,

Bryan L. Roth,

Raymond C. Stevens,

ZhiJie Liu

Publication year - 2018

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2018.01.001

Subject(s) - 5 ht2c receptor , g protein coupled receptor , ritanserin , biology , functional selectivity , receptor , drug discovery , inverse agonist , computational biology , agonist , pharmacology , neuroscience , bioinformatics , 5 ht receptor , serotonin , genetics

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-HT 2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT 2C 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-HT 2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT 2A-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.

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