Login / Signup

Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone.

Dohyun ImAsuka InoueTakaaki FujiwaraTakanori NakaneYasuaki YamanakaTomoko UemuraChihiro MoriYuki ShiimuraKanako Terakado KimuraHidetsugu AsadaNorimichi NomuraTomoyuki TanakaAyumi YamashitaEriko NangoKensuke TonoFrancois Marie Ngako KadjiJunken AokiSo IwataTatsuro Shimamura
Published in: Nature communications (2020)
In addition to the serotonin 5-HT2A receptor (5-HT2AR), the dopamine D2 receptor (D2R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D2R have been described in complex with the inverse agonists risperidone (D2Rris) and haloperidol (D2Rhal). Here we describe the structure of human D2R in complex with spiperone (D2Rspi). In D2Rspi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D2Rris and D2Rhal, demonstrating that ECL2 in D2R is highly dynamic. Moreover, D2Rspi exhibited an extended binding pocket to accommodate spiperone's phenyl ring, which probably contributes to the selectivity of spiperone to D2R and 5-HT2AR. Together with D2Rris and D2Rhal, the structural information of D2Rspi should be of value for designing novel antipsychotics with improved safety and efficacy.
Keyphrases
  • endothelial cells
  • binding protein
  • bipolar disorder
  • high resolution
  • molecular dynamics simulations
  • induced pluripotent stem cells
  • mass spectrometry
  • social media
  • combination therapy
  • crystal structure