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 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 flexib

SUBMITTER: Harris JA 

PROVIDER: S-EPMC8712391 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature