Structural features for functional selectivity at serotonin receptors

Science. 2013 May 3;340(6132):615-9. doi: 10.1126/science.1232808. Epub 2013 Mar 21.


Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.

Publication types

  • Comparative Study
  • 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

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Arrestin / metabolism
  • Arrestins / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Ergolines / chemistry
  • Ergolines / metabolism
  • Ergotamine / chemistry
  • Ergotamine / metabolism*
  • HEK293 Cells
  • Humans
  • Ligands
  • Lysergic Acid Diethylamide / chemistry
  • Lysergic Acid Diethylamide / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Protein Structure, Secondary
  • Receptor, Serotonin, 5-HT1B / chemistry
  • Receptor, Serotonin, 5-HT1B / metabolism*
  • Receptor, Serotonin, 5-HT2B / chemistry*
  • Receptor, Serotonin, 5-HT2B / metabolism*
  • Receptors, Serotonin / chemistry
  • Receptors, Serotonin / metabolism
  • Signal Transduction
  • beta-Arrestins


  • Arrestin
  • Arrestins
  • Ergolines
  • HTR1B protein, human
  • Ligands
  • Receptor, Serotonin, 5-HT1B
  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin
  • beta-Arrestins
  • Lysergic Acid Diethylamide
  • Ergotamine

Associated data

  • PDB/4IB4