5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology
| Autor: | Suwen Zhao, Raymond C. Stevens, Walden E. Bjørn-Yoshimoto, Lu Qu, Xi Ping Huang, Jianjun Cheng, Vsevolod Katritch, Kang Ding, Michael A. Hanson, Zhi-Jie Liu, Anders A. Jensen, Petr Popov, Yao Peng, Mengchen Pu, Ling Shen, Daniel Wacker, Louise F. Nikolajsen, John D. McCorvy, Shuguang Yuan, Gye Won Han, Tao Che, Katherine Lansu, David E. Gloriam, Bryan L. Roth, Kasper Harpsøe, Yiran Wu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist Drug discovery medicine.drug_class Ritanserin Computational biology Biology General Biochemistry Genetics and Molecular Biology 5-HT2C receptor 03 medical and health sciences 030104 developmental biology medicine Functional selectivity Inverse agonist Receptor G protein-coupled receptor medicine.drug |
| Zdroj: | Cell. 172:719-730.e14 |
| ISSN: | 0092-8674 |
| Popis: | 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-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 A and 2.7 A, 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. |
| Databáze: | OpenAIRE |
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