Coding GPCR-G protein specificity

Furness, Sebastian G.B.; Sexton, Patrick M.

doi:10.1038/cr.2017.92

Cited by 11 publications

(4 citation statements)

References 10 publications

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“…This will improve efforts to model the dynamics of coupling selectivity. Still, in previous reporting by us and others, the H5 helix is shown to be sufficient for altering the selectivity of GPCRs to specific G proteins 7 , 8 , 14 , 33 , 41 , 47 , 48 .…”

Section: Discussionmentioning

confidence: 78%

Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

Sandhu

Cho

et al. 2022

Nat Commun

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Recent studies have shown that G protein coupled receptors (GPCRs) show selective and promiscuous coupling to different Gα protein subfamilies and yet the mechanisms of the range of coupling preferences remain unclear. Here, we use Molecular Dynamics (MD) simulations on ten GPCR:G protein complexes and show that the location (spatial) and duration (temporal) of intermolecular contacts at the GPCR:Gα protein interface play a critical role in how GPCRs selectively interact with G proteins. We identify that some GPCR:G protein interface contacts are common across Gα subfamilies and others specific to Gα subfamilies. Using large scale data analysis techniques on the MD simulation snapshots we derive a spatio-temporal code for contacts that confer G protein selective coupling and validated these contacts using G protein activation BRET assays. Our results demonstrate that promiscuous GPCRs show persistent sampling of the common contacts more than G protein specific contacts. These findings suggest that GPCRs maintain contact with G proteins through a common central interface, while the selectivity comes from G protein specific contacts at the periphery of the interface.

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Section: Discussionmentioning

confidence: 78%

Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

Sandhu

Cho

et al. 2022

Nat Commun

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“…In addition, spectroscopic approaches, like single‐molecule FRET and NMR, will be needed to investigate whether the conformational transitions of the receptor and the transducer are directly coupled to each other and to identify the allosteric pathways that are involved in the ligand‐dependent regulation of transducer conformations. Together, these studies will not only help us to better understand the mechanistic principle of partial and biased signaling but will also increase our knowledge about the coupling selectivity of GPCRs for different G protein and arrestin isotypes, which is currently only poorly understood [6,30,153,193–195].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

The role of structural dynamics in GPCR‐mediated signaling

Hilger

2021

The FEBS Journal

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G protein-coupled receptors (GPCRs) play critical roles in the regulation of human physiology in response to a wide array of different extracellular stimuli and thus represent one of the largest groups of therapeutic drug targets. Recent advances in the structural characterization of GPCRs in different conformations and in complex with G proteins and arrestins have provided important insights into the mechanism and function of GPCRs. However, in order to truly understand the molecular basis of the functional versatility of GPCRs, the structural snapshots obtained by X-ray crystallography or cryo-EM need to be complimented with information about the conformational dynamics of receptors and their signaling complexes. In the last decade, a combination of biophysical approaches and computational studies has been utilized to examine the molecular motions of GPCRs and their transducer complexes and how they are regulated by ligands of different efficacy and bias. These studies revealed that GPCRs are highly dynamic allosteric proteins that can sample multiple conformational states. Ligands with distinct signaling profiles not only impact the conformational landscape of GPCRs but also of the receptor-engaged G proteins and arrestins. The conformational dynamics of GPCRs and their signaling complexes and the ligand-dependent bias sampling of distinct functional states are important underlying principles behind the complex signaling behavior of GPCRs.

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“…GPCRs play a crucial role in neuronal and non-neuronal tissues in shaping both immune and avoidance behavioral responses toward invading pathogens (48). In this study, we investigated the dual functionality of GPCR/NPR-15 in regulating molecular innate immunity and pathogen avoidance behavior independently of aerotaxis.…”

Section: Discussionmentioning

confidence: 99%

Neuronal NPR-15 modulates molecular and behavioral immune responses via the amphid sensory neuron-intestinal axis inC. elegans

Otarigho

Butts

Aballay

2023

Preprint

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The survival of hosts during infections relies on their ability to mount effective molecular and behavioral immune responses. Despite extensive research on these defense strategies in various species, including the model organism Caenorhabditis elegans, the neural mechanisms underlying their interplay remain poorly understood. Previous studies have highlighted the role of neural G protein-coupled receptors (GPCRs) in regulating both immunity and pathogen avoidance, which is particularly dependent on aerotaxis. To address this knowledge gap, we conducted a screen of mutants in neuropeptide receptor family genes. We found that loss-of-function mutations in npr-15 activated immunity while suppressing pathogen avoidance behavior. Through further analysis, NPR-15 was found to regulate immunity by modulating the activity of key transcription factors, namely GATA/ELT-2 and TFEB/HLH-30. Surprisingly, the lack of pathogen avoidance of npr-15 mutant animals was not influenced by oxygen levels. Moreover, our studies revealed that the amphid sensory neuron ASJ is involved in mediating the immune and behavioral responses orchestrated by NPR-15. Additionally, NPR-15 was found to regulate avoidance behavior via the TRPM gene, GON-2, which may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance. Overall, this study expands our knowledge of how neuronal GPCRs can simultaneously modulate immunity and behavior. Given the conserved nature of the GPCR and immune signaling pathways studied, the findings contribute to a broader understanding of host defense strategies and mechanism underlining the interplay between immunity and behavior across species.

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Coding GPCR-G protein specificity

Cited by 11 publications

References 10 publications

Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity

The role of structural dynamics in GPCR‐mediated signaling

Neuronal NPR-15 modulates molecular and behavioral immune responses via the amphid sensory neuron-intestinal axis inC. elegans

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