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

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...

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Vydáno v:Nature communications Ročník 11; číslo 1; s. 6442 - 11
Hlavní autoři: Im, Dohyun, Inoue, Asuka, Fujiwara, Takaaki, Nakane, Takanori, Yamanaka, Yasuaki, Uemura, Tomoko, Mori, Chihiro, Shiimura, Yuki, Kimura, Kanako Terakado, Asada, Hidetsugu, Nomura, Norimichi, Tanaka, Tomoyuki, Yamashita, Ayumi, Nango, Eriko, Tono, Kensuke, Kadji, Francois Marie Ngako, Aoki, Junken, Iwata, So, Shimamura, Tatsuro
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 22.12.2020
Nature Publishing Group
Nature Portfolio
Témata:
101/1
631/45/612/194
631/535
631/535/1266
82/80
82/83
Antipsychotics
Binding
Conformation
Crystal structure
Dopamine
Dopamine D2 receptors
G protein-coupled receptors
Haloperidol
Humanities and Social Sciences
Inverse agonists
Mental disorders
multidisciplinary
Psychotropic drugs
Receptors
Risperidone
Schizophrenia
Science
Science (multidisciplinary)
Selectivity
Serotonin
Serotonin S2 receptors
Spiperone
Therapeutic targets
ISSN:2041-1723, 2041-1723
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Shrnutí: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. The dopamine D 2 receptor (D 2 R) is a GPCR and an important drug target for schizophrenia treatment. Here, the authors present the crystal structure of human D 2 R in complex with the antipsychotic drug spiperone, which is of interest for designing antipsychotics with improved receptor selectivity.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-20221-0