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

Cell. 2018 Feb 8;172(4):719-730.e14. doi: 10.1016/j.cell.2018.01.001. Epub 2018 Feb 1.

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.

Keywords: GPCR; crystal structures; ergotamine; polypharmacology; ritanserin; selectivity; serotonin 2C receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ergotamine / chemistry*
  • HEK293 Cells
  • Humans
  • Obesity / drug therapy
  • Obesity / metabolism
  • Protein Domains
  • Receptor, Serotonin, 5-HT2C / chemistry*
  • Receptor, Serotonin, 5-HT2C / metabolism
  • Ritanserin / chemistry*
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism
  • Serotonin 5-HT2 Receptor Agonists / chemistry*
  • Serotonin 5-HT2 Receptor Antagonists / chemistry*
  • Structure-Activity Relationship
  • Substance-Related Disorders / drug therapy
  • Substance-Related Disorders / metabolism

Substances

  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin 5-HT2 Receptor Antagonists
  • Ritanserin
  • Ergotamine