Faculty Opinions recommendation of Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor.

AbstractMigration of mature dendritic cells (DCs) to lymph nodes is critical for the initiation of adaptive immunity. While CCR7, a a G-protein-coupled receptor for CCL19/21 chemokines, is known to be essential for chemotaxis of mature DCs, the molecular mechanism linking inflammation to chemotaxis remains unclear. We previously demonstrated that fascin1, an actin-bundling protein, increases chemotaxis of mature DCs. In this paper we showed that fascin1 enhanced Interleukin (IL)-6 secretion and signaling. Furthermore, we demonstrated that IL-6 signaling is required for chemotaxis. Blockage of IL-6 signaling in WT DCs with an anti-IL-6 receptorα (IL-6Rα) antibody inhibited chemotaxis toward CCL19. Likewise, knockout (KO) of IL-6Rα inhibited chemotaxis of BMDCs. The addition of soluble IL-6Rα and IL-6 rescued chemotaxis of IL-6Rα KO BMDCs, underscoring the role of IL-6 signaling in chemotaxis. We found that IL-6 signaling is required for internalization of CCR7, the initial step of CCR7 recycling. CCR7 recycling is known to be essential for CCR7-mediated chemotaxis, explaining why IL-6 signaling is needed for chemotaxis of mature DCs. Our results have identified IL-6 signaling as a new regulatory pathway for CCR7/CCL19-mediated chemotaxis, and suggest that rapid migration of mature DCs to lymph nodes depends on inflammation-associated IL-6 signaling.

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Molecular Mechanism for Inhibition of G Protein-Coupled Receptor Kinase 2 by a Selective RNA Aptamer

Structure ◽

10.1016/j.str.2012.05.002 ◽

2012 ◽

Vol 20 (8) ◽

pp. 1300-1309 ◽

Cited By ~ 32

Author(s):

Valerie M. Tesmer ◽

Sabine Lennarz ◽

Günter Mayer ◽

John J.G. Tesmer

Keyword(s):

G Protein ◽

Molecular Mechanism ◽

Rna Aptamer ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Molecular mechanism of biased signaling in a prototypical G protein–coupled receptor

Science ◽

10.1126/science.aaz0326 ◽

2020 ◽

Vol 367 (6480) ◽

pp. 881-887 ◽

Cited By ~ 21

Author(s):

Carl-Mikael Suomivuori ◽

Naomi R. Latorraca ◽

Laura M. Wingler ◽

Stephan Eismann ◽

Matthew C. King ◽

...

Keyword(s):

G Protein ◽

Protein A ◽

Binding Pocket ◽

Great Promise ◽

G Protein Coupled Receptor ◽

Structural Mechanism ◽

Biased Signaling ◽

Dynamics Simulations ◽

Effective Drugs ◽

G Protein Coupled

Biased signaling, in which different ligands that bind to the same G protein–coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.

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A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor

Molecular Pharmacology ◽

10.1124/mol.116.107276 ◽

2017 ◽

Vol 91 (4) ◽

pp. 348-356 ◽

Cited By ~ 7

Author(s):

Anna De Min ◽

Carlo Matera ◽

Andreas Bock ◽

Janine Holze ◽

Jessica Kloeckner ◽

...

Keyword(s):

G Protein ◽

Molecular Mechanism ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery

International Journal of Molecular Sciences ◽

10.3390/ijms20174237 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4237 ◽

Cited By ~ 3

Author(s):

Zou ◽

Ewalt ◽

Ng

Keyword(s):

Molecular Dynamics ◽

Drug Discovery ◽

G Protein ◽

Drug Targets ◽

Conformational Dynamics ◽

Md Simulations ◽

Data Bank ◽

G Protein Coupled Receptor ◽

Biased Signaling ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. Some ligands that bind to GPCRs activate different downstream signaling pathways. G protein activation, or -arrestin biased signaling, involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. -arrestin biased signaling has become a hot target for structure-based drug discovery. However, challenges include that there are few crystal structures available in the Protein Data Bank and that GPCRs are highly dynamic. Hence, molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators’ interactions with receptors and ligands. Here, we highlight recent MD simulation studies and enhanced sampling methods used to study biased G protein-coupled receptor signaling and their conformational dynamics as well as applications to drug discovery.

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