Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone
Dohyun Im, Asuka Inoue, Takaaki Fujiwara, Takanori Nakane, Yasuaki Yamanaka, Tomoko Uemura, Chihiro Mori, Yuki Shiimura, Kanako Kimura, Hidetsugu Asada, Norimichi Nomura, Tomoyuki Tanaka, A. Yamashita, Eriko Nango, Kensuke Tono, Francois Marie Ngako Kadji, Junken Aoki, So Iwata, Tatsuro Shimamura
Abstract
Abstract In addition to the serotonin 5-HT 2A receptor (5-HT 2A R), the dopamine D 2 receptor (D 2 R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D 2 R have been described in complex with the inverse agonists risperidone (D 2 R ris ) and haloperidol (D 2 R hal ). Here we describe the structure of human D 2 R in complex with spiperone (D 2 R spi ). In D 2 R spi , the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D 2 R ris and D 2 R hal , demonstrating that ECL2 in D 2 R is highly dynamic. Moreover, D 2 R spi exhibited an extended binding pocket to accommodate spiperone’s phenyl ring, which probably contributes to the selectivity of spiperone to D 2 R and 5-HT 2A R. Together with D 2 R ris and D 2 R hal , the structural information of D 2 R spi should be of value for designing novel antipsychotics with improved safety and efficacy.