Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, CA, USA.
Nat Chem Biol. 2022 Jan;18(1):109-115. doi: 10.1038/s41589-021-00890-8. Epub 2021 Oct 28.
The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G and G proteins. Neurokinin A also activates NK1R, but leads to selective G signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryogenic-electron microscopy structures of active NK1R bound to SP or the G-biased peptide SP6-11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent G signaling but not G signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6-11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.
神经肽物质 P（SP）在疼痛和炎症中很重要。SP 通过 G 和 G 蛋白激活神经激肽-1 受体（NK1R）进行信号转导。神经激肽 A 也能激活 NK1R，但导致选择性 G 信号转导。两种刺激如何在同一 G 蛋白偶联受体上产生不同的 G 蛋白信号转导仍不清楚。我们确定了与 SP 或 G 偏向肽 SP6-11 结合的活性 NK1R 的低温电子显微镜结构。NK1R 内的肽相互作用对受体激活至关重要。相反，SP 和 NK1R 细胞外环之间的相互作用对于有效的 G 信号转导但不是 G 信号转导是必需的。分子动力学模拟表明，这些表面接触限制了 SP 的灵活性。与 NK1R 结合时，缺乏这些相互作用的 SP6-11 是动态的。因此，NK1R 激动剂的结构动力学取决于与受体细胞外环的相互作用，并调节 G 蛋白信号转导的选择性。其他神经肽与其同源受体之间的类似相互作用可能会调节细胞内信号转导。
