scholarly journals Topological control of cytokine receptor signaling induces differential effects in hematopoiesis

Science ◽  
2019 ◽  
Vol 364 (6442) ◽  
pp. eaav7532 ◽  
Author(s):  
Kritika Mohan ◽  
George Ueda ◽  
Ah Ram Kim ◽  
Kevin M. Jude ◽  
Jorge A. Fallas ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
G Protein Coupled Receptors ◽  
Erythropoietin Receptor ◽  
Cytokine Receptor ◽  
Receptor Signaling ◽  
Biased Agonism ◽  
Pharmacological Modulation ◽  
G Protein Coupled ◽  
Complex Crystal ◽  
Important Cytokine

Although tunable signaling by G protein–coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. This surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.

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 Integrating High-Content Analysis into a Multiplexed Screening Approach to Identify and Characterize GPCR Agonists

2014 ◽  
Vol 19 (7) ◽  
pp. 1079-1089 ◽  
Author(s):  
Yingjie Zhu ◽  
John Watson ◽  
Mengjie Chen ◽  
Ding Ren Shen ◽  
Melissa Yarde ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein Coupled Receptors ◽  
High Content Imaging ◽  
Biased Agonism ◽  
Receptor Oligomerization ◽  
Sphingosine 1 Phosphate ◽  
High Content Analysis ◽  
Screening Assays ◽  
Hit Identification ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are one of the most popular and proven target classes for therapeutic intervention. The increased appreciation for allosteric modulation, receptor oligomerization, and biased agonism has led to the development of new assay platforms that seek to capitalize on these aspects of GPCR biology. High-content screening is particularly well suited for GPCR drug discovery given the ability to image and quantify changes in multiple cellular parameters, to resolve subcellular structures, and to monitor events within a physiologically relevant environment. Focusing on the sphingosine-1-phosphate (S1P1) receptor, we evaluated the utility of high-content approaches in hit identification efforts by developing and applying assays to monitor β-arrestin translocation, GPCR internalization, and GPCR recycling kinetics. Using these approaches in combination with more traditional GPCR screening assays, we identified compounds whose unique pharmacological profiles would have gone unnoticed if using a single platform. In addition, we identified a compound that induces an atypical pattern of β-arrestin translocation and GPCR recycling kinetics. Our results highlight the value of high-content imaging in GPCR drug discovery efforts and emphasize the value of a multiassay approach to study pharmacological properties of compounds of interest.

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

scholarly journals S1P/S1P Receptor Signaling in Neuromuscolar Disorders

2019 ◽  
Vol 20 (24) ◽  
pp. 6364 ◽  
Author(s):  
Elisabetta Meacci ◽  
Mercedes Garcia-Gil
Keyword(s):  
Neuromuscular Diseases ◽  
Clinical Applications ◽  
G Protein Coupled Receptors ◽  
Receptor Signaling ◽  
Charcot Marie Tooth Disease ◽  
System Degeneration ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
G Protein Coupled ◽  
Tooth Disease

The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot–Marie–Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.

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

scholarly journals Drosophila GoLoco-Protein Pins Is a Target of Gαo-mediated G Protein–coupled Receptor Signaling

2009 ◽  
Vol 20 (17) ◽  
pp. 3865-3877 ◽  
Author(s):  
Damir Kopein ◽  
Vladimir L. Katanaev
Keyword(s):  
G Protein ◽  
System Development ◽  
Nervous System Development ◽  
G Protein Coupled Receptors ◽  
Guanine Nucleotide ◽  
Receptor Signaling ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Necessary And Sufficient ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) transduce their signals through trimeric G proteins, inducing guanine nucleotide exchange on their Gα-subunits; the resulting Gα-GTP transmits the signal further inside the cell. GoLoco domains present in many proteins play important roles in multiple trimeric G protein–dependent activities, physically binding Gα-subunits of the Gαi/o class. In most cases GoLoco binds exclusively to the GDP-loaded form of the Gα-subunits. Here we demonstrate that the poly-GoLoco–containing protein Pins of Drosophila can bind to both GDP- and GTP-forms of Drosophila Gαo. We identify Pins GoLoco domain 1 as necessary and sufficient for this unusual interaction with Gαo-GTP. We further pinpoint a lysine residue located centrally in this domain as necessary for the interaction. Our studies thus identify Drosophila Pins as a target of Gαo-mediated GPCR receptor signaling, e.g., in the context of the nervous system development, where Gαo acts downstream from Frizzled and redundantly with Gαi to control the asymmetry of cell divisions.

scholarly journals The complex role of Prostaglandin E2-EP receptor signaling in wound healing

2020 ◽  
Author(s):  
Kristy E. Gilman ◽  
Kirsten H. Limesand
Keyword(s):  
Wound Healing ◽  
G Protein ◽  
Lipid Mediators ◽  
G Protein Coupled Receptors ◽  
Prostaglandin E ◽  
Receptor Signaling ◽  
Wound Healing Response ◽  
Ep Receptor ◽  
G Protein Coupled

Prostaglandins are critical lipid mediators involved in the wound healing response, with prostaglandin E2 (PGE2) being the most complex and exhibiting the most diverse physiological outputs. PGE2 signals via four G-protein coupled receptors, termed EP-receptors 1-4, that induce distinct signaling pathways upon activation and lead to an array of different outputs. Recent studies examining the role of PGE2 and EP receptor signaling in wound healing following various forms of tissue damage are discussed in this review.

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