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Title | Selective G protein signaling driven by substance P-neurokinin receptor dynamics. |
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Journal, issue, pages | Nat Chem Biol, Vol. 18, Issue 1, Page 109-115, Year 2022 |
Publish date | Oct 28, 2021 |
Authors | Julian A Harris / Bryan Faust / Arisbel B Gondin / Marc André Dämgen / Carl-Mikael Suomivuori / Nicholas A Veldhuis / Yifan Cheng / Ron O Dror / David M Thal / Aashish Manglik / |
PubMed Abstract | 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 ...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. |
External links | Nat Chem Biol / PubMed:34711980 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.0 - 3.2 Å |
Structure data | EMDB-24569, PDB-7rmg: EMDB-24570, PDB-7rmh: EMDB-24572, PDB-7rmi: |
Source |
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Keywords | SIGNALING PROTEIN/MEMBRANE PROTEIN / Substance P / G protein / GPCR / Neurokinin / Tachykinin / SIGNALING PROTEIN / SIGNALING PROTEIN-MEMBRANE PROTEIN complex |