Biased Agonism at G Protein-Coupled Receptors: The Promise and the Challenges-A Medicinal Chemistry Perspective

2014 ◽  
Vol 34 (6) ◽  
pp. 1286-1330 ◽  
Author(s):  
Jeremy Shonberg ◽  
Laura Lopez ◽  
Peter J. Scammells ◽  
Arthur Christopoulos ◽  
Ben Capuano ◽  
...  
Keyword(s):  
G Protein ◽  
Medicinal Chemistry ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
G Protein Coupled

Novel Insights into Biased Agonism at G Protein-Coupled Receptors and their Potential for Drug Design

2013 ◽  
Vol 19 (28) ◽  
pp. 5156-5166 ◽  
Author(s):  
Maria Marti-Solano ◽  
Ramon Guixa-Gonzalez ◽  
Ferran Sanz ◽  
Manuel Pastor ◽  
Jana Selent
Keyword(s):  
Drug Design ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
G Protein Coupled

scholarly journals A Novel Method for Analyzing Extremely Biased Agonism at G Protein–Coupled Receptors

2015 ◽  
Vol 87 (5) ◽  
pp. 866-877 ◽  
Author(s):  
Edward L. Stahl ◽  
Lei Zhou ◽  
Frederick J. Ehlert ◽  
Laura M. Bohn
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
Novel Method ◽  
G Protein Coupled

scholarly journals A Practical Guide to Approaching Biased Agonism at G Protein Coupled Receptors

2017 ◽  
Vol 11 ◽  
Author(s):  
Jaimee Gundry ◽  
Rachel Glenn ◽  
Priya Alagesan ◽  
Sudarshan Rajagopal
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
Practical Guide ◽  
G Protein Coupled

Allostery and Biased Agonism at Class B G Protein-Coupled Receptors

2016 ◽  
Vol 117 (1) ◽  
pp. 111-138 ◽  
Author(s):  
Denise Wootten ◽  
Laurence J. Miller ◽  
Cassandra Koole ◽  
Arthur Christopoulos ◽  
Patrick M. Sexton
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
Class B ◽  
G Protein Coupled

scholarly journals Differential GRK Recruitment and the Phosphorylation Barcode as a Mechanism for Biased Agonism at G Protein‐Coupled Receptors

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Julia Gardner ◽  
Dylan Eiger ◽  
Christopher Honeycutt ◽  
Noelia Boldizsar ◽  
Issac Choi ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
G Protein Coupled

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

2020 ◽  
Author(s):  
Kevin Zheng ◽  
Jeffrey S. Smith ◽  
Anmol Warman ◽  
Issac Choi ◽  
Jaimee N. Gundry ◽  
...  
Keyword(s):  
Complex Formation ◽  
Signaling Pathway ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Surface Receptors ◽  
Biased Agonism ◽  
G Protein Coupled

AbstractG-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:β-arrestin 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.

Sign in / Sign up

Export Citation Format

Share Document