EMD-24572
SP6-11 biased agonist bound to active human neurokinin 1 receptor in complex with miniGs/q70
EMD-24572
Single-particle3.2 Å
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Map released: 03/11/2021
Last modified: 13/11/2024
Sample Organism:
Homo sapiens,
synthetic construct,
Lama glama
Sample: Substance P bound to Neurokinin 1 receptor-miniGs/q70 complex
Fitted models: 7rmi (Avg. Q-score: 0.458)
Raw data: EMPIAR-10786
Deposition Authors: Harris JA, Faust B
Sample: Substance P bound to Neurokinin 1 receptor-miniGs/q70 complex
Fitted models: 7rmi (Avg. Q-score: 0.458)
Raw data: EMPIAR-10786
Deposition Authors: Harris JA, Faust B
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Selective G protein signaling driven by substance P-neurokinin receptor dynamics.
Harris JA,
Faust B
,
Gondin AB
,
Damgen MA
,
Suomivuori CM
,
Veldhuis NA,
Cheng Y
,
Dror RO
,
Thal DM
,
Manglik A
(2022) Nat Chem Biol , 18 , 109 - 115
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(2022) Nat Chem Biol , 18 , 109 - 115
Abstract:
The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via Gq and Gs proteins. Neurokinin A also activates NK1R, but leads to selective Gq 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 Gq-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 Gs signaling but not Gq 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.
The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via Gq and Gs proteins. Neurokinin A also activates NK1R, but leads to selective Gq 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 Gq-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 Gs signaling but not Gq 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.