A conformation-equilibrium model captures ligand-ligand interactions and ligand-biased signalling by G-protein coupled receptors

FEBS Journal ◽  
2014 ◽  
Vol 281 (20) ◽  
pp. 4659-4671 ◽  
Author(s):  
Susanne Roth ◽  
Frank J. Bruggeman
Keyword(s):  
G Protein ◽  
Equilibrium Model ◽  
G Protein Coupled Receptors ◽  
Conformation Equilibrium ◽  
Ligand Interactions ◽  
G Protein Coupled

scholarly journals Emerging roles of adhesion G protein-coupled receptors

2021 ◽  
Author(s):  
Matthew Rosa ◽  
Timothy Noel ◽  
Matthew Harris ◽  
Graham Ladds
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Current Knowledge ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Extracellular Region ◽  
Extracellular Matrix Components ◽  
Ligand Interactions ◽  
Tethered Ligand ◽  
G Protein Coupled

Adhesion G protein-coupled receptors (aGPCRs) form a sub-group within the GPCR superfamily. Their distinctive structure contains an abnormally large N-terminal, extracellular region with a GPCR autoproteolysis-inducing (GAIN) domain. In most aGPCRs, the GAIN domain constitutively cleaves the receptor into two fragments. This process is often required for aGPCR signalling. Over the last two decades, much research has focussed on aGPCR-ligand interactions, in an attempt to deorphanize the family. Most ligands have been found to bind to regions N-terminal to the GAIN domain. These receptors may bind a variety of ligands, ranging across membrane-bound proteins and extracellular matrix components. Recent advancements have revealed a conserved method of aGPCR activation involving a tethered ligand within the GAIN domain. Evidence for this comes from increased activity in receptor mutants exposing the tethered ligand. As a result, G protein-coupling partners of aGPCRs have been more extensively characterised, making use of their tethered ligand to create constitutively active mutants. This has led to demonstrations of aGPCR function in, for example, neurodevelopment and tumour growth. However, questions remain around the ligands that may bind many aGPCRs, how this binding is translated into changes in the GAIN domain, and the exact mechanism of aGPCR activation following GAIN domain conformational changes. This review aims to examine the current knowledge around aGPCR activation, including ligand binding sites, the mechanism of GAIN domain-mediated receptor activation and how aGPCR transmembrane domains may relate to activation. Other aspects of aGPCR signalling will be touched upon, such as downstream effectors and physiological roles.

scholarly journals DCyFIR: a high-throughput CRISPR platform for multiplexed G protein-coupled receptor profiling and ligand discovery

2020 ◽  
Author(s):  
NJ Kapolka ◽  
GJ Taghon ◽  
JB Rowe ◽  
WM Morgan ◽  
JF Enten ◽  
...  
Keyword(s):  
G Protein ◽  
High Throughput ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Yeast Genome ◽  
Innovative Technology ◽  
Ligand Discovery ◽  
Ligand Interactions ◽  
Approved Drugs ◽  
G Protein Coupled

AbstractMore than 800 G protein-coupled receptors (GPCRs) comprise the largest class of membrane receptors in humans. While there is ample biological understanding and many approved drugs for prototypic GPCRs, most GPCRs still lack well-defined biological ligands and drugs. Here, we report our efforts to tap the potential of understudied GPCRs by developing yeast-based technologies for high-throughput CRISPR engineering and GPCR ligand discovery. We refer to these technologies collectively as Dynamic Cyan induction by Functional Integrated Receptors: DCyFIR. A major advantage of DCyFIR is that GPCRs and other assay components are CRISPR-integrated directly into the yeast genome, making it possible to decode ligand specificity by profiling mixtures of GPCR-barcoded yeast strains in a single tube. To demonstrate the capabilities of DCyFIR, we engineered a yeast strain library of 30 human GPCRs and their 300 possible GPCR-Gα coupling combinations. Profiling of these 300 strains, using parallel (DCyFIRscreen) and multiplex (DCyFIRplex) DCyFIR modes, recapitulated known GPCR agonism with 100% accuracy, and identified unexpected interactions for the receptors ADRA2B, HCAR3, MTNR1A, S1PR1, and S1PR2. To demonstrate DCyFIR scalability, we profiled a library of 320 human metabolites and observed new GPCR-ligand interactions with amino acid, lipid, sugar, and steroid metabolites. Remarkably, many of these findings pertained to understudied “pharmacologically dark” receptors GPR4, GPR65, GPR68, and HCAR3. For example, we found that kynurenic acid activated HCAR3 with a nearly 20-fold lower EC50 than GPR35, its known receptor. Taken together, these findings demonstrate the power of DCyFIR for identifying novel ligand interactions with prototypic and understudied GPCRs.Significance StatementG protein-coupled receptors (GPCRs) are the largest class of membrane receptors in humans. As such, GPCR signaling is central to human biology and medicine. While more than 30% of approved drugs target roughly 150 GPCRs, most receptors lack well-defined endogenous ligands and are currently not druggable. To address this challenge, we created a GPCR screening platform for ligand and drug discovery. This innovative technology enables the cost-effective profiling of ligands and drug compounds against mixtures of hundreds of GPCR-barcoded cell strains in a single experiment. Because a ligand or drug is tested against a collection of receptors all at once, our novel method accelerates the process of identifying potential GPCR ligands and drugs.

scholarly journals Detecting ligand interactions with G protein-coupled receptors in real-time on living cells

2013 ◽  
Vol 441 (4) ◽  
pp. 820-824 ◽  
Author(s):  
Bo Xu ◽  
Zohreh Varasteh ◽  
Anna Orlova ◽  
Karl Andersson ◽  
Dan Larhammar ◽  
...  
Keyword(s):  
Real Time ◽  
G Protein ◽  
Living Cells ◽  
G Protein Coupled Receptors ◽  
Ligand Interactions ◽  
G Protein Coupled
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