2021
DOI: 10.1038/s41589-021-00890-8
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Selective G protein signaling driven by substance P–neurokinin receptor dynamics

Abstract: 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 cryo-EM structures of active NK1R bound to SP or the G q -biased peptide SP… Show more

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Cited by 64 publications
(63 citation statements)
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“…Most recently, solved structures of receptors bound to nucleotide-free G proteins have been used to predict residues in the receptor-G protein interface that contribute to selectivity. These studies have provided valuable insights into how individual receptors discriminate G protein subtypes, and collectively suggest that the conformation of the receptor-G protein complexes that are critical for selective coupling share many features with these empty-state complexes [5][6][7][8] . Nevertheless, it is recognized that structural studies are generally limited to stable complexes that exist only after GDP release, and that such complexes may not reflect the key intermediates that immediately precede nucleotide release.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…Most recently, solved structures of receptors bound to nucleotide-free G proteins have been used to predict residues in the receptor-G protein interface that contribute to selectivity. These studies have provided valuable insights into how individual receptors discriminate G protein subtypes, and collectively suggest that the conformation of the receptor-G protein complexes that are critical for selective coupling share many features with these empty-state complexes [5][6][7][8] . Nevertheless, it is recognized that structural studies are generally limited to stable complexes that exist only after GDP release, and that such complexes may not reflect the key intermediates that immediately precede nucleotide release.…”
Section: Discussionmentioning
confidence: 99%
“…The mechanistic basis of coupling selectivity has been studied extensively using receptor and G protein chimeras and site-directed mutagenesis 3,4 . More recently, structural characterization of GPCR-G protein complexes has identified elements that are important for activation of specific G proteins [5][6][7][8] . However, structural studies require stable agonist-receptor-G protein ternary complexes, and this almost always requires a nucleotide-free G protein.…”
Section: Introductionmentioning
confidence: 99%
“…S3 ). In the structure of the NKA-bound NK2R–G q complex, ECL2 mainly interacts with the first two N-terminal residues His1 and Lys2 of NKA, while in the recently reported SP-bound NK1R–G q structure, R177 of ECL2 forms an extended hydrogen-bond interaction with the side chain of N96 2.68 and the main-chain carbonyl oxygen of Gln6 of SP 8 , 9 (Fig. 1l ).…”
mentioning
confidence: 87%
“…The N-termini of tachykinins are critical regions associated with their subtype selectivity 8 . The structure shows that the N-terminus of NKA is mainly stabilized by ECL2 of the receptor (Fig.…”
mentioning
confidence: 99%
“…Supplementary materials can be found at . References [ 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ] are cited in the supplementary materials.…”
mentioning
confidence: 99%