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Structures of neurokinin 1 receptor in complex with G_q and G_s proteins reveal substance P binding mode and unique activation features.

ABSTRACT: 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, 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 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.

SUBMITTER: Thom C

PROVIDER: S-EPMC8654284 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Structures of neurokinin 1 receptor in complex with Gq and Gs proteins reveal substance P binding mode and unique activation features.

Thom Cristian C Ehrenmann Janosch J Vacca Santiago S Waltenspühl Yann Y Schöppe Jendrik J Medalia Ohad O Plückthun Andreas A

Science advances 20211208 50

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 ext ...[more]

PMID: 34878828

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Project description:BackgroundTachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including neurotransmission, nociception, inflammation, smooth muscle contractility, and stimulation of endocrine and exocrine gland secretion. Their abnormal expression has been reported to be associated with neurological disorders, inflammation, and cancer. Even though NKs are expressed in the same cells with their expression being inversely correlated in some conditions, there is no direct evidence to prove their interaction. Understanding the functional crosstalk between NKs in mediated downstream signaling and cellular responses may elucidate the roles of each receptor in pathophysiology.ResultsIn this study, we showed that NKs were co-expressed in some cells. However, different from NK3, which only forms homodimerization, we demonstrated a direct interaction between NK1 and NK2 at the protein level using co-immunoprecipitation and NanoBiT-based protein interaction analysis. Through heterodimerization, NK2 downregulated substance P-stimulated NK1 signals, such as intracellular Ca2+ mobilization and ERK phosphorylation, by enhancing β-arrestin recruitment, even at the ligand concentration that could not activate NK2 itself or in the presence of NK1 specific antagonist, aprepitant. In A549 cells with receptors deleted and reconstituted, NK2 exerted a negative effect on substance P/NK1-mediated cell migration.ConclusionOur study has provided the first direct evidence of an interaction between NK1 and NK2, which highlights the functional relevance of their heterodimerization in cellular responses. Our findings demonstrated that through dimerization, NK2 exerts negative effects on downstream signaling and cellular response mediated by NK1. Moreover, this study has significant implications for understanding the complexity of GPCR dimerization and its effect on downstream signaling and cellular responses. Given the important roles of tachykinins and NKs in pathophysiology, these insights may provide clues for developing NKs-targeting drugs.

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Structures of neurokinin 1 receptor in complex with G_q and G_s proteins reveal substance P binding mode and unique activation features.

Publications

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.

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