Structures of neurokinin 1 receptor in complex with G<sub>q</sub> and G<sub>s</sub> proteins reveal substance P binding mode and unique activation features.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34878828.
- Also identified by DOI 10.1126/sciadv.abk2872 and PMC identifier 8654284.
- Licence recorded as CC BY-NC.
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Abstract
The neurokinin 1 receptor (NK<sub>1</sub>R) is involved in inflammation and pain transmission. This pathophysiologically important G protein–coupled receptor is predominantly activated by its cognate agonist substance P (SP) but also by the closely related neurokinins A and B. Here, we report cryo–electron microscopy structures of SP-bound NK<sub>1</sub>R in complex with its primary downstream signal mediators, G<sub>q</sub> and G<sub>s</sub>. Our structures reveal how a polar network at the extracellular, solvent-exposed receptor surface shapes the orthosteric pocket and that NK<sub>1</sub>R adopts a noncanonical active-state conformation with an interface for G protein binding, which is distinct from previously reported structures. Detailed comparisons with antagonist-bound NK<sub>1</sub>R crystal structures reveal that insurmountable antagonists induce a distinct and long-lasting receptor conformation that sterically blocks SP binding. Together, our structures provide important structural insights into ligand and G protein promiscuity, the lack of basal signaling, and agonist- and antagonist-induced conformations in the neurokinin receptor family.