Structures of neurokinin 1 receptor in complex with G
| Autor: | Cristian, Thom, Janosch, Ehrenmann, Santiago, Vacca, Yann, Waltenspühl, Jendrik, Schöppe, Ohad, Medalia, Andreas, Plückthun |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | Description Neuropeptide-bound NK1R:G protein complex structures explain mechanisms ranging from insurmountable antagonism to activation. The neurokinin 1 receptor (NK1R) 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 NK1R in complex with its primary downstream signal mediators, Gq and Gs. Our structures reveal how a polar network at the extracellular, solvent-exposed receptor surface shapes the orthosteric pocket and that NK1R 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 NK1R 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. |
| Databáze: | OpenAIRE |
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