Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR

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

doi:10.1126/science.aay9813

Cited by 162 publications

(210 citation statements)

References 48 publications

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“…The biased agonism hypothesis has two key tenets: (a) biased agonists stabilize receptor conformations distinct from full agonists and the result is differential coupling to receptor interacting proteins; (b) the response to GPCR activation arises from many cellular pathways and differential coupling to G proteins, GPCR kinases (GRKs), and β‐arrestins can preferentially activate one pathway over another 12,18,19 . Recent biophysical, structural, and cell biological studies have provided important support to this model 20–25 . Thus, a G protein biased agonist will have greater relative efficacy in activation of the heterotrimeric G protein and subsequent signaling cascades 26 .…”

Section: Classical Pharmacology and An Introduction To Biasmentioning

confidence: 99%

A cellular perspective of bias at G protein‐coupled receptors

2020

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G protein-coupled receptors (GPCRs) modulate cell function over short-and long-term timescales. GPCR signaling depends on biochemical parameters that define the what, when, and where of receptor function: what proteins mediate and regulate receptor signaling, where within the cell these interactions occur,and how long these interactions persist. These parameters can vary significantly depending on the activating ligand. Collectivity, differential agonist activity at a GPCR is called bias or functional selectivity. Here we review agonist bias at GPCRs with a focus on ligands that show dramatically different cellular responses from their unbiased counterparts.

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Section: Classical Pharmacology and An Introduction To Biasmentioning

confidence: 99%

A cellular perspective of bias at G protein‐coupled receptors

2020

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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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“…In this inward orientation, it can participate in the coordination of the sodium ion and thus in the stabilization of the inactive state 68,69 . By contrast, the g-rotamer of N3.35, directed outward, has been observed in the active conformation of three CXCR4 related receptors, the μ opioid receptor 70 , and the AngII receptors AT1 71 and AT2 72,73 . These data suggest that the orientation of N3.35 may be an important feature of receptor activation.…”

Section: Discussionmentioning

confidence: 89%

Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations

Taddese

Garnier

Abdi

et al. 2020

Sci Rep

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The dynamic structure of proteins is essential for their functions and may include large conformational transitions which can be studied by molecular dynamics (MD) simulations. However, details of these transitions are difficult to automatically track. To facilitate their analysis, we developed two scores of correlation between sidechain dihedral angles. The CIRCULAR and OMES scores are computed from, respectively, dihedral angle values and rotamer distributions. As a case study, we applied our methods to an activation-like transition of the chemokine receptor CXCR4, observed during accelerated MD simulations. The principal component analysis of the correlation matrices was consistent with the networking structure of the top ranking pairs. Both scores identify a set of residues whose “collaborative” sidechain rotamerization immediately preceded or accompanied the conformational transition of CXCR4. Detailed analysis of the sequential order of these rotamerizations suggests that an allosteric mechanism, involving the outward motion of an asparagine residue in transmembrane helix 3, might be a prerequisite to the large scale conformational transition of CXCR4. This case study provides the proof-of-concept that the correlation methods developed here are valuable exploratory techniques to help decipher complex reactional pathways.

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Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR

Cited by 162 publications

References 48 publications

A cellular perspective of bias at G protein‐coupled receptors

A cellular perspective of bias at G protein‐coupled receptors

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

Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations

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Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR

Cited by 162 publications

References 48 publications

A cellular perspective of bias at G protein‐coupled receptors

A cellular perspective of bias at G protein‐coupled receptors

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

Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations

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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