Structure of the dopamine D(2) receptor in complex with the antipsychotic drug spiperone.
Structure of the dopamine D(2) receptor in complex with the antipsychotic drug spiperone.
复制标题
多巴胺D（2）受体与抗精神病药物螺哌隆复合物的结构。
DOI：
10.1038/s41467-020-20221-0
复制
发表时间：
2020-12-22
影响因子：
16.6
通讯作者：
Shimamura T
中科院分区：
文献类型：
--
作者：
Im D;Inoue A;Fujiwara T;Nakane T;Yamanaka Y;Uemura T;Mori C;Shiimura Y;Kimura KT;Asada H;Nomura N;Tanaka T;Yamashita A;Nango E;Tono K;Kadji FMN;Aoki J;Iwata S;Shimamura T
除5-羟色胺5-HT2A受体（5-HT2AR）外，多巴胺D2受体（D2R）是抗精神病药物治疗精神分裂症的关键治疗靶点。D2R的无活性状态结构已被描述为与反向激动剂利培酮（D2Rris）和氟哌啶醇（D2Rhal）的复合物。本文描述了人类D2R与spiperone复合物（D2Rspi）的结构。在D2Rspi中，构成配体结合袋的细胞外环（ECL） 2的构象与D2Rris和D2Rhal有很大不同，表明D2R中的ECL2是高度动态的。此外，D2Rspi显示出一个扩展的结合袋，以容纳spiperone的苯环，这可能有助于spiperone对D2R和5-HT2AR的选择性。D2Rspi与D2Rris和D2Rhal的结构信息对设计安全性和有效性更高的新型抗精神病药物具有重要价值。多巴胺D2受体（D2R）是一种GPCR，是治疗精神分裂症的重要药物靶点。在这里，作者介绍了人类D2R与抗精神病药物spiperone配合物的晶体结构，这对设计具有更高受体选择性的抗精神病药物具有重要意义。
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. The dopamine D2 receptor (D2R) is a GPCR and an important drug target for schizophrenia treatment. Here, the authors present the crystal structure of human D2R in complex with the antipsychotic drug spiperone, which is of interest for designing antipsychotics with improved receptor selectivity.
登录
查看更多内容
影响因子：
6.1
作者：
KEBABIAN, JW
通讯作者：
KEBABIAN, JW
DOI：
10.1016/0922-4106(92)90129-j
发表时间：
1992-10-01
期刊：
EUROPEAN JOURNAL OF PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION
影响因子：
--
作者：
MANSOUR, A;MENG, F;AKIL, H
通讯作者：
AKIL, H
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
6.1
作者：
Barty A;Kirian RA;Maia FR;Hantke M;Yoon CH;White TA;Chapman H
通讯作者：
Chapman H
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC