Extended Data Fig. 4: Structural hallmarks of NK1R activation.
From: Selective G protein signaling driven by substance P–neurokinin receptor dynamics
(a) Alignment of the SP-NK1R-miniGs/q70 structure with an inactive-state NK1R structure (PDB: 6HLP24) reveals rearrangement of NK1R structural motifs indicative of class A GPCR activation, including: (b) displacement of the W6.48 ‘toggle-switch’ and (c) rearrangement of the ‘P5.50I3.40F6.44’ connector motif. (d) The non-canonical E782.50-N3017.49 interaction in NK1R is unchanged between inactive- and active-state structures. We compared the NK1R E782.50-N3017.49 interaction to the D2.50-N7.49 interaction in three class A neuropeptide-binding GPCRs, including: (e) the μ-opioid receptor (Active PDB: 5C1M17, Inactive PDB: 4DKL18), (f) the neurotensin 1 receptor (Active PDB: 6OS922, Inactive PDB: 4BUO23), and (g) the orexin 2 receptor (Active PDB: 7L1U, Inactive PDB: 5WQC). Alignment of the SP-NK1R-miniGs/q70 structure with (h) canonical (PDB: 6OS922) and (i) ‘non-canonical’ (PDB: 6OSA22) active-state NTS1R reveals that the miniGs/q70 protein adopts the canonical G protein coupling orientation.
