Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography
Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography
复制标题
NMR和晶体学研究拮抗剂药物阿瑞吡坦的人P物质受体结合模式
DOI：
10.1038/s41467-019-08568-5
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发表时间：
2019-02-07
影响因子：
16.6
通讯作者：
Zhao, Qiang
中科院分区：
文献类型：
--
作者：
Chen, Shuanghong;Lu, Mengjie;Zhao, Qiang
神经激肽1受体(NK1R)在中枢和外周神经系统中具有关键的调节功能，NK1R拮抗剂如Approant已被批准用于治疗化疗引起的恶心和呕吐。然而，缺乏关于NK1R结构和生化的数据限制了针对该受体的进一步药物开发。在这里，我们结合核磁共振光谱和X射线结晶学提供了与人NK1R变异体的络合物中的显着体结合模式的动态和静态表征。19F-核磁共振显示结合位处有一个缓慢的失速率，在那里显着者占据了多个亚态，这些亚态与频率在毫秒范围内交换。结合配体的环境受2.50位氨基酸的影响，该位氨基酸在A类GPCRs的配体结合和受体信号转导中起关键作用。晶体结构现在揭示了受体信号如何与跨膜螺旋VII中保守的NP7.50xxY基序的构象有关。
Neurokinin 1 receptor (NK1R) has key regulating functions in the central and peripheral nervous systems, and NK1R antagonists such as aprepitant have been approved for treating chemotherapy-induced nausea and vomiting. However, the lack of data on NK1R structure and biochemistry has limited further drug development targeting this receptor. Here, we combine NMR spectroscopy and X-ray crystallography to provide dynamic and static characterisation of the binding mode of aprepitant in complexes with human NK1R variants.19F-NMR showed a slow off-rate in the binding site, where aprepitant occupies multiple substates that exchange with frequencies in the millisecond range. The environment of the bound ligand is affected by the amino acid in position 2.50, which plays a key role in ligand binding and receptor signaling in class A GPCRs. Crystal structures now reveal how receptor signaling relates to the conformation of the conserved NP7.50xxY motif in transmembrane helix VII.