Structural determinants of 5-HT2B receptor activation and biased agonism

Nat Struct Mol Biol. 2018 Sep;25(9):787-796. doi: 10.1038/s41594-018-0116-7. Epub 2018 Aug 20.


Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor-the human 5-HT2B receptor-in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.

Publication types

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

MeSH terms

  • Binding Sites
  • Humans
  • Ligands
  • Mutagenesis
  • Protein Conformation
  • Receptor, Serotonin, 5-HT2B / chemistry*
  • Receptor, Serotonin, 5-HT2B / drug effects*
  • Serotonin Receptor Agonists / pharmacology*
  • Signal Transduction


  • Ligands
  • Receptor, Serotonin, 5-HT2B
  • Serotonin Receptor Agonists