State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Nat Commun. 2019 Feb 7;10(1):638. doi: 10.1038/s41467-019-08568-5.
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. F-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 NPxxY motif in transmembrane helix VII.
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，如阿瑞匹坦，已被批准用于治疗化疗引起的恶心和呕吐。然而，由于缺乏 NK1R 结构和生物化学方面的数据，限制了针对该受体的进一步药物开发。在这里，我们结合 NMR 光谱和 X 射线晶体学，提供了阿瑞匹坦与人 NK1R 变体复合物结合模式的动态和静态特征。F-NMR 显示在结合部位的离解速率较慢，其中阿瑞匹坦占据多个亚状态，以毫秒级的频率进行交换。结合配体的环境受位置 2.50 处氨基酸的影响，该氨基酸在配体结合和 A 类 GPCR 中的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转导如何与跨膜螺旋 VII 中的保守 NPxxY 基序的构象相关。
