1. 5-HT 2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.
- Author
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Peng Y, McCorvy JD, Harpsøe K, Lansu K, Yuan S, Popov P, Qu L, Pu M, Che T, Nikolajsen LF, Huang XP, Wu Y, Shen L, Bjørn-Yoshimoto WE, Ding K, Wacker D, Han GW, Cheng J, Katritch V, Jensen AA, Hanson MA, Zhao S, Gloriam DE, Roth BL, Stevens RC, and Liu ZJ
- Subjects
- HEK293 Cells, Humans, Obesity drug therapy, Obesity metabolism, Protein Domains, Receptor, Serotonin, 5-HT2C metabolism, Schizophrenia drug therapy, Schizophrenia metabolism, Structure-Activity Relationship, Substance-Related Disorders drug therapy, Substance-Related Disorders metabolism, Ergotamine chemistry, Receptor, Serotonin, 5-HT2C chemistry, Ritanserin chemistry, Serotonin 5-HT2 Receptor Agonists chemistry, Serotonin 5-HT2 Receptor Antagonists chemistry
- Abstract
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-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., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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