7p02

Publication Abstract from PubMed

The neurokinin 1 receptor (NK(1)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(1)R in complex with its primary downstream signal mediators, G(q) and G(s). Our structures reveal how a polar network at the extracellular, solvent-exposed receptor surface shapes the orthosteric pocket and that NK(1)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(1)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.

Structures of neurokinin 1 receptor in complex with G(q) and G(s) proteins reveal substance P binding mode and unique activation features.,Thom C, Ehrenmann J, Vacca S, Waltenspuhl Y, Schoppe J, Medalia O, Pluckthun A Sci Adv. 2021 Dec 10;7(50):eabk2872. doi: 10.1126/sciadv.abk2872. Epub 2021 Dec , 8. PMID:34878828^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.