7P00

Human Neurokinin 1 receptor (NK1R) substance P Gq chimera (mGsqi) complex

Summary for 7P00

• Entry DOI: 10.2210/pdb7p00/pdb
• EMDB information: 13140
• Descriptor: Antibody fragment scFv16, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: receptor, complex, eukaryotic protein, membrane protein
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 6
• Total formula weight: 153615.19

Authors

Thom, C.,Ehrenmann, J.,Vacca, S.,Waltenspuhl, Y.,Schoppe, J.,Medalia, O.,Pluckthun, A. (deposition date: 2021-06-29, release date: 2021-12-15, Last modification date: 2025-07-02)

Primary citation

Thom, C.,Ehrenmann, J.,Vacca, S.,Waltenspuhl, Y.,Schoppe, J.,Medalia, O.,Pluckthun, A.
Structures of neurokinin 1 receptor in complex with G q and G s proteins reveal substance P binding mode and unique activation features.
Sci Adv, 7:eabk2872-eabk2872, 2021

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

PubMed: 34878828
DOI: 10.1126/sciadv.abk2872

Experimental method

ELECTRON MICROSCOPY (2.71 Å)