Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine

Nat Struct Mol Biol. 2019 Feb;26(2):121-128. doi: 10.1038/s41594-018-0180-z. Epub 2019 Feb 4.


Many drugs target the serotonin 2A receptor (5-HT2AR), including second-generation antipsychotics that also target the dopamine D2 receptor (D2R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT2AR in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT2AR is structurally similar to 5-HT2CR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT2AR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT2AR significantly differs around extracellular loops 1 and 2 from that in D2R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT2AR-selective drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / metabolism*
  • Dibenzothiepins / chemistry*
  • Dibenzothiepins / metabolism*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Molecular Structure
  • Protein Structure, Secondary
  • Receptor, Serotonin, 5-HT2A / chemistry*
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Risperidone / chemistry*
  • Risperidone / metabolism*


  • Antipsychotic Agents
  • Dibenzothiepins
  • Receptor, Serotonin, 5-HT2A
  • Risperidone
  • zotepine