Molecular Mechanism of Biased Signaling in a Prototypical G-protein-coupled Receptor

Suomivuori, Carl‐Mikael; Latorraca, Naomi R.; Wingler, Laura M.; Eismann, Stephan; King, Matthew C.; Kleinhenz, Alissa L. W.; Skiba, Meredith A.; Staus, Dean P.; Kruse, Andrew C.; Lefkowitz, Robert J.; Dror, Ron O.

doi:10.1016/j.bpj.2019.11.1000

Cited by 22 publications

(27 citation statements)

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“…Besides their therapeutic importance, AT 1 receptors are paradigmatic for studying the molecular nature of biased agonism. Numerous Ga q/11 (e.g., TRV055 and TRV056) and b-arrestin-biased agonists (e.g., TRV023 TRV026) have been reported [43] and the structural basis and dynamics of their biased agonism have been elucidated recently [96][97][98][99]. A key structural element of all biased angiotensin analogues is the nature of the amino acid at position 8 which binds deep in the orthosteric pocket (a phenylalanine in angiotensin II, the endogenous agonist).…”

Section: Angiotensin Receptorsmentioning

confidence: 99%

Allosteric coupling and biased agonism in G protein‐coupled receptors

Böck

Bermudez

2021

The FEBS Journal

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G protein-coupled receptors (GPCRs) are essential cell membrane signaling molecules and represent the most important class of drug targets. Some signaling pathways downstream of a GPCR may be responsible for drug adverse effects, while others mediate therapeutic efficacy. Biased ligands preferentially activate only a subset of all GPCR signaling pathways. They hold great potential to become next-generation GPCR drugs with less side effects due to their potential to exclusively activate desired signaling pathways. However, the molecular basis of biased agonism is poorly understood. GPCR activation occurs through allosteric coupling, the propagation of conformational changes from the extracellular ligand-binding pocket to the intracellular G protein-binding interface. Comparison of GPCR structures in complex with G proteins or b-arrestin reveals that intracellular transducer coupling results in closure of the ligand-binding pocket trapping the agonist inside its binding site. Allosteric coupling appears to be transducer-specific offering the possibility of harnessing this mechanism for the design of biased ligands. Here, we review the biochemical, pharmacological, structural, and biophysical evidence for allosteric coupling and delineate that biased agonism should be a consequence of preferential allosteric coupling from the ligand-binding pocket to one transducer-binding site. As transducer binding leads to large structural rearrangements in the extracellular ligand-binding pocket, we survey biased ligands with an extended binding mode that interact with extracellular receptor domains. We propose that biased ligands use ligand-specific triggers inside the binding pocket that are relayed through preferential allosteric coupling to a specific transducer, eventually leading to biased signaling.

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Section: Angiotensin Receptorsmentioning

confidence: 99%

Allosteric coupling and biased agonism in G protein‐coupled receptors

Böck

Bermudez

2021

The FEBS Journal

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“…The specific conformations adopted by GPCRs, which preferentially allow coupling to distinct effectors, is likely a key determinant of which specific downstream signaling response is amplified (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist

Crilly

Weinberg

et al. 2021

Preprint

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The prevailing model for the variety in drug responses is that they stabilize distinct active states of their G protein-coupled receptor (GPCR) targets, allowing coupling to different effectors. However, whether the same ligand can produce different GPCR active states based on the environment of receptors in cells is a fundamental unanswered question. Here we address this question using live cell imaging of conformational biosensors that read out distinct active conformations of the δ-opioid receptor (DOR), a physiologically relevant GPCR localized to Golgi and the surface in neurons. We show that, although Golgi and surface pools of DOR regulated cAMP, the two pools engaged distinct conformational biosensors in response to the same ligand. Further, DOR recruited arrestin on the plasma membrane but not the Golgi. Our results suggest that the same agonist drives different conformations of a GPCR at different locations, allowing receptor coupling to distinct effectors at different locations.

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“…These data suggest conformational differences in how CXCL11, VUF10661, and VUF11418 induce Gαi:β-arrestin:CXCR3 complexes, with VUF10661 and VUF11418 producing a more similar tripartite complex conformation than CXCL11. It is likely that these agonists induce different CXCR3 free energy landscapes, similar to that observed at other GPCRs (50)(51)(52)(53), but further work will be necessary to confirm this.…”

Section: Discussionmentioning

confidence: 77%

Biased agonists of the chemokine receptor CXCR3 differentially drive formation of G_αi:β-arrestin complexes

Zheng¹,

Smith

Warman³

et al. 2020

Preprint

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G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, signal through the proximal effectors G proteins and β-arrestins to influence nearly every biological process. Classically, the G protein and β-arrestin signaling pathways have largely been considered separable. Recently, direct interactions between Gα protein and β-arrestin have been described and suggest a distinct GPCR signaling pathway. Within these newly described Gα:β-arrestin complexes, Gαi/o, but not other Gα protein subtypes, have been appreciated to directly interact with β-arrestin, regardless of canonical GPCR Gα protein subtype coupling. However it is unclear how biased agonists differentially regulate this newly described Gαi:βarrestin interaction, if at all. Here we report that endogenous ligands (chemokines) of the GPCR CXCR3, CXCL9, CXCL10, and CXCL11, along with two small molecule biased CXCR3 agonists, differentially promote the formation of Gαi:β-arrestin complexes. The ability of CXCR3 agonists to form Gαi:β-arrestin complexes does not correlate well with either G protein signaling or β-arrestin recruitment. Conformational biosensors demonstrate that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We find these Gαi:β-arrestin complexes can associate with CXCR3, but not with ERK. These findings further support that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of biased agonism.

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Molecular Mechanism of Biased Signaling in a Prototypical G-protein-coupled Receptor

Cited by 22 publications

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Allosteric coupling and biased agonism in G protein‐coupled receptors

Allosteric coupling and biased agonism in G protein‐coupled receptors

Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist

Biased agonists of the chemokine receptor CXCR3 differentially drive formation of G_αi:β-arrestin complexes

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Molecular Mechanism of Biased Signaling in a Prototypical G-protein-coupled Receptor

Cited by 22 publications

References 0 publications

Allosteric coupling and biased agonism in G protein‐coupled receptors

Allosteric coupling and biased agonism in G protein‐coupled receptors

Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist

Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes

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Product

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Biased agonists of the chemokine receptor CXCR3 differentially drive formation of G_αi:β-arrestin complexes