期刊
NATURE CHEMICAL BIOLOGY
卷 18, 期 1, 页码 109-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00890-8
关键词
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资金
- National Institutes of Health (NIH) [1R35GM140847, DP5OD023048, R01GM127359, S10OD020054, S10OD021741]
- National Health and Medical Research Council (NHMRC) [APP1138448, APP1196951]
- Australian Research Council DECRA [DE170100152]
- Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology
- National Science Foundation Graduate Research Fellowship Program [2034836]
- Human Frontier Science Program [LT000916/2018-L]
- NIH Common Fund Transformative High-Resolution Cryo-Electron Microscopy program [U24 GM129541]
- Pew Charitable Trusts
- Esther and A. & Joseph Klingenstein Fund
- Searle Scholars Program
- Directorate for STEM Education
- Division Of Graduate Education [2034836] Funding Source: National Science Foundation
- Australian Research Council [DE170100152] Funding Source: Australian Research Council
The neuropeptide substance P activates the neurokinin-1 receptor through interactions deep within the receptor, while interactions between the neuropeptide and the receptor extracellular loops regulate G protein signaling selectivity. This study sheds light on how different stimuli can lead to distinct G protein signaling at the same receptor.
The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G(q) and G(s) proteins. Neurokinin A also activates NK1R, but leads to selective G(q) 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(q) -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(s) signaling but not G(q) 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.
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