Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine
Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine
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DOI：
10.1038/s41594-018-0180-z
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发表时间：
2019-02-01
影响因子：
16.8
通讯作者：
Shimamura, Tatsuro
中科院分区：
文献类型：
--
作者：
Kimura, Kanako Terakado;Asada, Hidetsugu;Shimamura, Tatsuro
许多药物针对5-羟色胺2A受体(5-HT2AR)，包括第二代抗精神病药物，也针对多巴胺D-2受体(D2R)。由于与其他胺能受体的非选择性结合，这些药物通常会产生严重的副作用。在这里，我们报告了人类5-HT2AR与第二代抗精神病药物利培酮和佐特平的复合体的结构。这些抗精神病药物通过与配体结合口袋底部的残基形成直接接触而有效地稳定了不活跃的构象，这些残基的运动对受体的激活是重要的。5-HT2AR在结构上与5-HT2CR相似，但在正构体结合部位附近有一个独特的侧向延伸的空腔。对接研究和诱变研究表明，高度选择性的5-HT2AR拮抗剂结合了侧面扩展的空洞。5-HT2AR细胞外环1和2周围的配体结合口袋的构象与D2R的明显不同。这些发现有助于合理设计更安全的抗精神病药物和5-HT2AR选择性药物。
Many drugs target the serotonin 2A receptor (5-HT2AR), including second-generation antipsychotics that also target the dopamine D-2 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.