scholarly journals Conformational Dynamics of a G Protein-Coupled Receptor Opsin and Its Constitutively Active Mutant

2014 ◽  
Vol 54 (2) ◽  
pp. 111-112
Author(s):  
Hisao TSUKAMOTO
Keyword(s):  
G Protein ◽  
Conformational Dynamics ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Constitutively Active

Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation

Nature ◽  
1997 ◽  
Vol 385 (6614) ◽  
pp. 347-350 ◽  
Author(s):  
Leandros Arvanitakis ◽  
Elizabeth Geras-Raaka ◽  
Anjali Varma ◽  
Marvin C. Gershengorn ◽  
Ethel Cesarman
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Human Herpesvirus ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Constitutively Active

scholarly journals Quantitative assessment of constitutive G protein-coupled receptor activity with BRET-based G protein biosensors

2021 ◽  
Author(s):  
Hannes Schihada ◽  
Rawan Shekhani ◽  
Gunnar Schulte
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Mammalian Cells ◽  
Living Cells ◽  
Optical Biosensors ◽  
Heterotrimeric G Proteins ◽  
G Protein Coupled Receptor ◽  
Cellular Expression ◽  
G Protein Coupled ◽  
Constitutively Active

AbstractHeterotrimeric G proteins constitute the primary transducers of G protein-coupled receptor (GPCR) signaling. Besides mediating ligand-induced GPCR activation, G proteins transduce basal levels of activity in various physiological and pathophysiological settings evoked by constitutively active, native GPCRs or disease-related receptor mutants. Several generations of optical biosensors were developed and optimized to monitor GPCR ligand-induced G protein activation, however, quantitative approaches to detect constitutively active GPCRs are not available. Here, we designed and validated a set of eight bioluminescence-resonance-energy-transfer (BRET)-based G protein sensors, covering all four major families of G proteins, and established a protocol to identify constitutive GPCR/G protein signaling in living cells. These sensors rely on the encoding of all three G protein subunits on a single plasmid, enabling their cellular expression at desired relative levels and resulting in reduced signal variability in mammalian cells. Based on this sensor platform, we further present here an experimental protocol to quantify constitutive signaling of native and mutated GPCRs through these heterotrimeric transducers. This approach will aid in the characterization of constitutively active GPCRs and the exploration of their role in health and disease.One Sentence SummaryThis Resource article describes the validation of a biophysical approach to directly assess the constitutive signaling activity of G protein-coupled receptors through heterotrimeric G proteins in living cells using optical biosensors.

scholarly journals Identification of the First Nonpeptidergic Inverse Agonist for a Constitutively Active Viral-encoded G Protein-coupled Receptor

2002 ◽  
Vol 278 (7) ◽  
pp. 5172-5178 ◽  
Author(s):  
Paola Casarosa ◽  
Wiro M. Menge ◽  
Rosalba Minisini ◽  
Claas Otto ◽  
Jane van Heteren ◽  
...  
Keyword(s):  
G Protein ◽  
Inverse Agonist ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Constitutively Active

scholarly journals Conformational dynamics of a class C G-protein-coupled receptor

Nature ◽  
2015 ◽  
Vol 524 (7566) ◽  
pp. 497-501 ◽  
Author(s):  
Reza Vafabakhsh ◽  
Joshua Levitz ◽  
Ehud Y. Isacoff
Keyword(s):  
G Protein ◽  
Conformational Dynamics ◽  
G Protein Coupled Receptor ◽  
Class C ◽  
G Protein Coupled

scholarly journals Conformational Dynamics of a G Protein-Coupled Receptor at the Single-Molecule Level

2015 ◽  
Vol 108 (2) ◽  
pp. 350a
Author(s):  
Rajan Lamichhane ◽  
Jeffrey J. Liu ◽  
Raymond C. Stevens ◽  
David P. Millar
Keyword(s):  
G Protein ◽  
Single Molecule ◽  
Conformational Dynamics ◽  
G Protein Coupled Receptor ◽  
Single Molecule Level ◽  
G Protein Coupled

scholarly journals Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery

2019 ◽  
Vol 20 (17) ◽  
pp. 4237 ◽  
Author(s):  
Zou ◽  
Ewalt ◽  
Ng
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Data Bank ◽  
G Protein Coupled Receptor ◽  
Biased Signaling ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. Some ligands that bind to GPCRs activate different downstream signaling pathways. G protein activation, or -arrestin biased signaling, involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. -arrestin biased signaling has become a hot target for structure-based drug discovery. However, challenges include that there are few crystal structures available in the Protein Data Bank and that GPCRs are highly dynamic. Hence, molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators’ interactions with receptors and ligands. Here, we highlight recent MD simulation studies and enhanced sampling methods used to study biased G protein-coupled receptor signaling and their conformational dynamics as well as applications to drug discovery.

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