Allosteric coupling and biased agonism in G protein‐coupled receptors

Böck, Andreas; Bermudez, Marcel

doi:10.1111/febs.15783

Cited by 49 publications

(44 citation statements)

References 116 publications

(174 reference statements)

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“…Specifically, a ligand and transducer—binding from opposite sides of the cell membrane—may prefer the same receptor structure conformation and thereby allosterically select each other (Galandrin, Oligny‐Longpre, & Bouvier, 2007; Kenakin, 1995; Kenakin & Morgan, 1989; Roth & Chuang, 1987; Smith, Lefkowitz, & Rajagopal, 2018). In other words, this allosteric communication is reciprocal, as G protein pre‐coupling can potentiate agonist binding (Bock & Bermudez, 2021; De Lean, Stadel, & Lefkowitz, 1980; Lefkowitz, Mullikin, & Caron, 1976; Maguire, Van Arsdale, & Gliman, 1976). An activated receptor state has also been linked to a high affinity binding state for arrestin (Gurevich & Benovic, 1997).…”

Section: Introductionmentioning

confidence: 99%

Community guidelines for GPCR ligand bias: IUPHAR review 32

Kolb

Kenakin

Alexander

et al. 2022

British J Pharmacology

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138

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GPCRs modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Depending on which ligand activates a receptor, it can engage different intracellular transducers. This 'biased signalling' paradigm requires that we now characterize physiological signalling not just by receptors but by ligand-receptor pairs. Ligands eliciting biased signalling may constitute better drugs with higher efficacy and fewer adverse effects. However, ligand bias is very complex, making reproducibility and description challenging. Here, we provide guidelines and terminology for any scientists to design and report ligand bias experiments.The guidelines will aid consistency and clarity, as the basic receptor research and drug discovery communities continue to advance our understanding and exploitation of ligand bias. Scientific insight, biosensors, and analytical methods are still evolving and should benefit from and contribute to the implementation of the guidelines, together improving translation from in vitro to disease-relevant in vivo models. | INTRODUCTIONThe $800 human GPCRs transduce sensory inputs and systemic signals into appropriate cellular responses in numerous physiological processes. They recognize a vast diversity of signals ranging from photons, tastants and odours to ions, neurotransmitters, hormones, and cytokines (Harding et al., 2021;Wacker, Stevens, & Roth, 2017).Even though GPCRs represent the primary target of 34% of FDAapproved drugs, more than 220 non-olfactory GPCRs have disease associations which are as yet untapped in clinical research (Hauser, Attwood, Rask-Andersen, Schioth, & Gloriam, 2017;Sriram & Insel, 2018). Despite the diversity of extracellular ligands and physiological roles of GPCRs, these cell surface receptors share a conserved molecular fold and intracellular transducers. Agonist binding stabilizes active conformations of the receptor, facilitating the binding of one or more cytosolic transducer proteins. These include the heterotrimeric G proteins consisting of α, β and γ subunits that dissociate to α and βγ upon activation by the receptor. G proteins comprise 16 distinct α subunits and are divided into four families based on homology and associated downstream signalling pathways: G s (G s and

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Section: Introductionmentioning

confidence: 99%

Community guidelines for GPCR ligand bias: IUPHAR review 32

Kolb

Kenakin

Alexander

et al. 2022

British J Pharmacology

Self Cite

138

114

View full text Add to dashboard Cite

show abstract

“…Although GPCR represents the highly druggable targets, some signaling downstream of a GPCR may be responsible for drug adverse effects. Biased signals hold great promise to become next-generation GPCR drugs with less side effects due to their potential to preferentially activate desired signaling pathways [49] . Targeting CXCL12/CXCR7 biased signal would open a new avenue for improving drug designs to achieve higher e cacy and selectivity.…”

Section: Discussionmentioning

confidence: 99%

CXCL12/CXCR7/β-arrestin1 Biased Signal Promotes Epithelial-to-Mesenchymal Transition of Colorectal Cancer by Repressing Mirnas Through YAP1 Nuclear Translocation

Song

Wang

et al. 2021

Preprint

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Background: CXCR7 is an atypical chemokine receptor that transmits biased signal independent of G-protein activation. However, whether CXCL12/CXCR7 biased signal activation plays an essential role in colorectal cancer (CRC) progression and metastasis remains obscure. Methods: The functional role of CXCL12/CXCR7 biased signal in CRC was investigated by RNA-sequencing, Transwell assay and in vivo tumor xenografts. YAP1 nuclear translocation and molecular mechanisms were determined by cell transfection, luciferase activity assay, immunofluorescence, coimmunoprecipitation and immunohistochemistry and RT-qPCR analysis.Results: In this study, CXCR7 CXCL12/overexpression promotes Epithelial-to-mesenchymal transition (EMT) and upregulates the expression of stem marker doublecortin-like kinase 1 (DCLK1) in CRC cells with concurrent repression of miR-124-3p and miR-188-5p. Further luciferase assay prove that these miRNAs could regulate EMT by direct targeting vimentin and DCLK1. More importantly, CXCL12/CXCR7/β-arrestin1-mediated biased signal induces YAP1 nuclear translocation, which functions as a transcriptional repressor by interacting with Yin Yang 1 (YY1) and recruiting YY1 to the promoter of miR-124-3p and miR-188-5p. Pharmacological inhibitor of YAP1 recapitulates the anti-tumorigenesis and anti-metastasis effects of YAP1 depletion upon CXCR7 activation in tumor xenografts. Clinically, the expression of CXCR7 was positively correlated with nuclear YAP1 levels and EMT markers. Conclusions: Our findings revealed the novel role of YAP1 nuclear translocation in promoting EMT of CRC by repressing miR-124-3p and miR-188-5p through CXCL12/CXCR7/β-arrestin1 biased signal activation. These findings highlight the potential of targeting YAP1 nuclear translocation in hampering CXCL12/CXCR7 biased signal-induced metastasis of CRC.

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“…Opioid receptors belong to the large family of G protein-coupled receptors (GPCRs) [1]. GPCRs are membrane-embedded receptors that share a seven-transmembrane (7TM) helical structure and elicit a myriad of biological activities upon activation by endogenous or exogenous ligands [2][3][4]. Thus, GPCRs are widely addressed targets for drug development with around one-third of all approved drugs targeting GPCRs [5].…”

Section: Introductionmentioning

confidence: 99%

In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

et al. 2022

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Kappa-opioid receptor (KOR) antagonists are promising innovative therapeutics for the treatment of the central nervous system (CNS) disorders. The new scaffold opioid ligand, Compound A, was originally found as a mu-opioid receptor (MOR) antagonist but its binding/selectivity and activation profile at the KOR and delta-opioid receptor (DOR) remain elusive. In this study, we present an in vitro, in vivo and in silico characterization of Compound A by revealing this ligand as a KOR antagonist in vitro and in vivo. In the radioligand competitive binding assay, Compound A bound at the human KOR, albeit with moderate affinity, but with increased affinity than to the human MOR and without specific binding at the human DOR, thus displaying a preferential KOR selectivity profile. Following subcutaneous administration in mice, Compound A effectively reverse the antinociceptive effects of the prototypical KOR agonist, U50,488. In silico investigations were carried out to assess the structural determinants responsible for opioid receptor subtype selectivity of Compound A. Molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation revealed differences in the stabilization of the chlorophenyl moiety of Compound A within the opioid receptor binding pockets, rationalizing the experimentally determined binding affinity values. This new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics.

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Allosteric coupling and biased agonism in G protein‐coupled receptors

Cited by 49 publications

References 116 publications

Community guidelines for GPCR ligand bias: IUPHAR review 32

Community guidelines for GPCR ligand bias: IUPHAR review 32

CXCL12/CXCR7/β-arrestin1 Biased Signal Promotes Epithelial-to-Mesenchymal Transition of Colorectal Cancer by Repressing Mirnas Through YAP1 Nuclear Translocation

In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

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