Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
Nat Struct Mol Biol. 2019 Feb;26(2):121-128. doi: 10.1038/s41594-018-0180-z. Epub 2019 Feb 4.
Many drugs target the serotonin 2A receptor (5-HTR), including second-generation antipsychotics that also target the dopamine D receptor (DR). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HTR 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-HTR is structurally similar to 5-HTR but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HTR-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HTR significantly differs around extracellular loops 1 and 2 from that in DR. These findings are beneficial for the rational design of safer antipsychotics and 5-HTR-selective drugs.
许多药物都以血清素 2A 受体（5-HTR）为靶点，包括也针对多巴胺 D 受体（DR）的第二代抗精神病药。这些药物由于对其他单胺能受体的非选择性结合，常常产生严重的副作用。在这里，我们报告了人类 5-HTR 与第二代抗精神病药利培酮和佐替平复合物的结构。这些抗精神病药通过与配体结合口袋底部的残基形成直接接触，有效地稳定了非活性构象，这些残基的运动对于受体激活很重要。5-HTR 在结构上与 5-HTR 相似，但在正位结合位点附近具有独特的侧扩展腔。对接研究和突变研究表明，一种高度选择性的 5-HTR 拮抗剂结合在侧扩展腔内。5-HTR 中配体结合口袋的构象在细胞外环 1 和 2 周围与 DR 显著不同。这些发现有助于更合理地设计更安全的抗精神病药和 5-HTR 选择性药物。
