Biased agonism and allosteric modulation of G protein‐coupled receptor 183 – a 7TM receptor also known as Epstein–Barr virus‐induced gene 2

Daugvilaite, Viktorija; Madsen, Christian; Lückmann, Michael; Echeverria, Clara Castello; Sailer, Andreas W.; Frimurer, Thomas M.; Benned-Jensen, Tau

doi:10.1111/bph.13801

Cited by 13 publications

(16 citation statements)

References 59 publications

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“…This receptor is predominantly cell surface−expressed and internalizes constitutively as well as ligand dependently (after addition of the endogenous agonist 7α,25‐dihydroxycholesterol (7α,25‐OHC)) . Consistent with a previous report, 23.5% of surface‐expressed GPR183 was constitutively internalized after 30 min (Fig. F), whereas the addition of 7α,25‐OHC enhanced the internalization to 43% (Fig.…”

Section: Resultssupporting

confidence: 90%

Arrestin‐independent constitutive endocytosis of GPR125/ADGRA3

Spieß

Bagger

Torz

et al. 2019

Annals of the New York Academy of Sciences

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The orphan receptor GPR125 (ADGRA3) belongs to subgroup III of the adhesion G protein−coupled receptor (aGPCR) family. aGPCRs, also known as class B2 GPCRs, share basic structural and functional properties with other GPCRs. Many of them couple to G proteins and activate G protein−dependent and −independent signaling pathways, but little is known about aGPCR internalization and β-arrestin recruitment. GPR125 was originally described as a spermatogonial stem cell marker and studied for its role in Wnt signaling and cell polarity. Here, using cell-based assays and confocal microscopy, we show that GPR125 is expressed on the cell surface and undergoes constitutive endocytosis in a β-arrestin−independent, but clathrin-dependent manner, as indicated by colocalization with transferrin receptor 1, an early endosome marker. These data support that the constitutive internalization of GPR125 contributes to its biological functions by controlling receptor surface expression and accessibility for ligands. Our study sheds light on a new property of aGPCRs, namely internalization; a property described to be important for signal propagation, signal termination, and desensitization of class A (rhodopsin-like) and B1 (VIP/secretin) GPCRs.

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Section: Resultssupporting

confidence: 90%

Arrestin‐independent constitutive endocytosis of GPR125/ADGRA3

Spieß

Bagger

Torz

et al. 2019

Annals of the New York Academy of Sciences

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“…The recruitment of β-arrestin2 was measured using the PathHunter β-arrestin assay (DiscoverX) as described previously ( Daugvilaite et al, 2017 ). Briefy, cDNA encoding US28wt was fused to the ProLink C-terminal protein tag and the small fragment ofβ-galactose and cloned into pcDNA3.1+.…”

Section: Methodsmentioning

confidence: 99%

Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy

Miles

Spieß

Jude

et al. 2018

eLife

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Human cytomegalovirus has hijacked and evolved a human G-protein-coupled receptor into US28, which functions as a promiscuous chemokine 'sink’ to facilitate evasion of host immune responses. To probe the molecular basis of US28’s unique ligand cross-reactivity, we deep-sequenced CX3CL1 chemokine libraries selected on ‘molecular casts’ of the US28 active-state and find that US28 can engage thousands of distinct chemokine sequences, many of which elicit diverse signaling outcomes. The structure of a G-protein-biased CX3CL1-variant in complex with US28 revealed an entirely unique chemokine amino terminal peptide conformation and remodeled constellation of receptor-ligand interactions. Receptor signaling, however, is remarkably robust to mutational disruption of these interactions. Thus, US28 accommodates and functionally discriminates amongst highly degenerate chemokine sequences by sensing the steric bulk of the ligands, which distort both receptor extracellular loops and the walls of the ligand binding pocket to varying degrees, rather than requiring sequence-specific bonding chemistries for recognition and signaling.

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“…Similarly, for the b 2 -adrenoceptor, NMR studies have shown that "balanced" agonists for b 2 -adrenoceptors shift the ensemble equilibrium toward the G proteinspecific active state of helix 6 of the receptor, whereas b-arrestin-biased ligands regulate the conformational states in helix 7 . Similarly, bias SAR information regarding regions of receptors that are involved in biased signaling has also been obtained through site-directed mutagenesis as seen, for example, with G protein receptor 183 (Daugvilaite et al, 2017) and m-opioid receptors (Hothersall et al, 2017).…”

Section: Biased Receptor Signalingmentioning

confidence: 99%

“…For instance, the 5-HT 2A and b-adrenoceptor crystal structures have identified transmembrane domains specifically linked to biased ligand interaction (Warne et al, 2012;Wacker et al, 2013). Similarly, protein mutation has been employed to generate SAR data for biased signaling (G protein receptor 183, Daugvilaite et al, 2017;GLP-1, Wootten et al, 2016). Chemical scaffolds yielding biased molecules range from modification of natural endogenous agonists to natural products (Gupta et al, 2016).…”

Section: H Biased Signaling In Screening and Lead Optimizationmentioning

confidence: 99%

“…Therefore, the analysis usually uses a synthetic agonist as the reference to control for differences in receptor expression and centers on the impact of the mutation on the endogenous agonist. Ideally, specific residues may be identified in such studies to guide medicinal chemists to regions of the receptor that can change ligand selectivity (e.g., see Daugvilaite et al, 2017).…”

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confidence: 99%

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