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5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell 2018 Feb 08;172(4):719-730.e14

Date

02/06/2018

Pubmed ID

29398112

Pubmed Central ID

PMC6309861

DOI

10.1016/j.cell.2018.01.001

Scopus ID

2-s2.0-85041554345 (requires institutional sign-in at Scopus site)   208 Citations

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-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.

Author List

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, Liu ZJ

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Ergotamine
HEK293 Cells
Humans
Obesity
Protein Domains
Receptor, Serotonin, 5-HT2C
Ritanserin
Schizophrenia
Serotonin 5-HT2 Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists
Structure-Activity Relationship
Substance-Related Disorders