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TitleStructures of neurokinin 1 receptor in complex with G and G proteins reveal substance P binding mode and unique activation features.
Journal, issue, pagesSci Adv, Vol. 7, Issue 50, Page eabk2872, Year 2021
Publish dateDec 10, 2021
AuthorsCristian Thom / Janosch Ehrenmann / Santiago Vacca / Yann Waltenspühl / Jendrik Schöppe / Ohad Medalia / Andreas Plückthun /
PubMed AbstractThe 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 ...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.
External linksSci Adv / PubMed:34878828 / PubMed Central
MethodsEM (single particle)
Resolution2.71 - 2.87 Å
Structure data

EMDB-13140, PDB-7p00:
Human Neurokinin 1 receptor (NK1R) substance P Gq chimera (mGsqi) complex
Method: EM (single particle) / Resolution: 2.71 Å

EMDB-13141, PDB-7p02:
Human Neurokinin 1 receptor (NK1R) substance P Gs complex
Method: EM (single particle) / Resolution: 2.87 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Receptor / Complex / Eukaryotic protein

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