Molecular insights into the biased signaling mechanism of the μ-opioid receptor

Cong, Xiaojing; Maurel, Damien; Déméné, Hélène; Vasiliauskaité-Brooks, Ieva; Hagelberger, Joanna; Peysson, Fanny; Saint‐Paul, Julie; Golebiowski, Jérôme; Granier, Sébastien; Sounier, Rémy

doi:10.1016/j.molcel.2021.07.033

Cited by 46 publications

(39 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For GRK2 and GRK3 recruitment using BRET assay 107 , Venus-tagged PAFR and GRK2-Rluc or GRK3-Rluc were co-transfected into cells for at least 24 h. Before detection, cells were starved with PBS at 37 °C for 30 min. Afterward, the coelenterazine h substrate was added at a final concentration of 5 μM, and BRET signals were detected by Mithras LB940 with stimulation by PBS or an agonist.…”

Section: Methodsmentioning

confidence: 99%

Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

Liu

Tang

et al. 2022

Nat Commun

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are important drug targets that mediate various signaling pathways by activating G proteins and engaging β-arrestin proteins. Despite its importance for the development of therapeutics with fewer side effects, the underlying mechanism that controls the balance between these signaling modes of GPCRs remains largely unclear. Here, we show that assembly into dimers and oligomers can largely influence the signaling mode of the platelet-activating factor receptor (PAFR). Single-particle analysis results show that PAFR can form oligomers at low densities through two possible dimer interfaces. Stabilization of PAFR oligomers through cross-linking increases G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly. Reciprocally, β-arrestin prevents PAFR oligomerization. Our results highlight a mechanism involved in the control of receptor signaling, and thereby provide important insights into the relationship between GPCR oligomerization and downstream signaling.

show abstract

Section: Methodsmentioning

confidence: 99%

Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

Liu

Tang

et al. 2022

Nat Commun

View full text Add to dashboard Cite

show abstract

“…The authors found that a long-range allosteric network involving residues along helixes 2, 3, and 7 allows ligands in the extracellular binding pocket to favor one intracellular conformation over the other. Using a similar approach, Cong et al described differences in the dynamic and allosteric communications between the ligand-binding pocket and the receptor intracellular domains related to signaling bias in the μ-OR [ 26 ]. Interestingly, they observed that biased agonists trigger μ-OR conformational changes in the ICL1 and the H8, which may impair β-arrestin binding or signaling.…”

Section: Detection Of Allosteric Network In Gpcr Signalingmentioning

confidence: 99%

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Morales-Pastor¹,

Nerín-Fonz²,

Aranda-García³

et al. 2022

IJMS

View full text Add to dashboard Cite

Signaling bias is a promising characteristic of G protein-coupled receptors (GPCRs) as it provides the opportunity to develop more efficacious and safer drugs. This is because biased ligands can avoid the activation of pathways linked to side effects whilst still producing the desired therapeutic effect. In this respect, a deeper understanding of receptor dynamics and implicated allosteric communication networks in signaling bias can accelerate the research on novel biased drug candidates. In this review, we aim to provide an overview of computational methods and techniques for studying allosteric communication and signaling bias in GPCRs. This includes (i) the detection of allosteric communication networks and (ii) the application of network theory for extracting relevant information pipelines and highly communicated sites in GPCRs. We focus on the most recent research and highlight structural insights obtained based on the framework of allosteric communication networks and network theory for GPCR signaling bias.

show abstract

“…Here, to clarify the structural basis for MOR activation by the model allosteric modulator BMS-986122, we used NMR spectroscopy, which allows observation of biomolecules in solution ( 6 , 31 – 37 ), to analyze the dynamic structures and functions of MOR. Previously, Wüthrich’s group observed NMR signals from site-specifically modified 19 F-probes and revealed the conformational equilibrium in the β 2 -adrenergic receptor underlying the biased signaling pathway ( 38 ).…”

mentioning

confidence: 99%

Activation mechanism of the μ-opioid receptor by an allosteric modulator

Kaneko

Imai

Asao

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance The allosteric modulators, which bind to nonorthosteric sites to enhance the signaling activities of G-protein-coupled receptors (GPCRs), are new candidates for GPCR-targeting drugs. Our solution NMR analyses of the μ-opioid receptor (MOR) revealed that the MOR activity was determined by a conformational equilibrium between three conformations. Interestingly, an allosteric modulator shifted the equilibrium toward a conformation with the highest activity to a level that cannot be reached by orthosteric ligands alone, leading to the increased activity of MOR. Our NMR analyses also identified the binding site of the allosteric modulator, including the residues contributing to the regulation of the equilibrium. These findings provide insights into the rational developments of novel allosteric modulators.

show abstract

Molecular insights into the biased signaling mechanism of the μ-opioid receptor

Cited by 46 publications

References 87 publications

Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Activation mechanism of the μ-opioid receptor by an allosteric modulator

Contact Info

Product

Resources

About