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"Nicholson, Colin"
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Multiple intramolecular triggers converge to preferential G protein coupling in the CB2R
G protein-coupled receptors (GPCRs) are important therapeutic drug targets for a wide range of diseases. Upon activation, GPCRs can initiate several signaling pathways, each with unique therapeutic implications. Therefore, understanding how drugs selectively engage specific signaling pathways becomes paramount. However, achieving this selectivity remains highly challenging. To unravel the underlying multifaceted mechanisms, we integrate systematic mutagenesis of the CB
2
R, comprehensive profiling of G
αi2
and β-arrestin1 engagements and computer simulations to track the effects of mutations on receptor dynamics. Our research reveals multiple triggers within a complex allosteric communication network (ACN) that converge to preferential CB
2
R coupling by modulating evolutionarily conserved motifs. Utilizing network path analysis, we find that potent triggers are typically highly connected nodes and are located near regions of high information transmission within the ACN. Our insights highlight the complexity of GPCR signaling and provide a framework for the rational design of drug candidates tailored to evoke specific functional responses, ultimately enhancing the precision and efficacy of therapeutic interventions.
Nonselective engagement of GPCR signaling pathways by GPCR-targeting drugs can reduce treatment efficacy and cause side effects. The authors show that signaling selectivity in CB2R can be tuned by reshaping allosteric networks, offering insights for more precise therapies.
Journal Article
Agonist efficacy at the β2AR is driven by the faster association rate of the Gs protein
IntroductionThe β2-adrenoceptor (β2AR) is a class A G protein-coupled receptor (GPCR). It is therapeutically relevant in asthma and chronic obstructive pulmonary disease (COPD), where β2AR agonists relieve bronchoconstriction. The β2AR is a prototypical GPCR for structural and biophysical studies. However, the molecular basis of agonist efficacy at the β2AR is not understood. We hypothesised that the kinetics of GPCR–G protein interactions could play a role in determining ligand efficacy. By studying a range of agonists with varying efficacy, we examined the relationship between ligand-induced mini-Gs binding to the β2AR and ligand efficacy, along with the ability of individual ligands to activate the G protein in cells.MethodsWe used NanoBRET technology to measure ligand-induced binding of purified Venus-mini-Gs to β2AR-nLuc in membrane preparations under both equilibrium and kinetic conditions. In addition, we examined the ability of these β2AR agonists to activate the heterotrimeric Gs protein, measured using the Gs-CASE protein biosensor in living cells. This assay detects a reduction in NanoBRET between the nano-luciferase (nLuc) donor on the Gα subunit and Venus acceptor on the Gγ upon Gs protein activation.ResultsThe 12 β2AR agonists under study revealed a broad range of ligand potency and efficacy values in the cellular Gs-CASE assays. Kinetic characterisation of mini-Gs binding to the agonist β2AR complex revealed a strong correlation between ligand efficacy values (Emax) and mini-Gs affinity ( K d) and its association rate ( k on). In contrast, there was no correlation between ligand efficacy and reported ligand dissociation rates (or residence times).ConclusionThe association rate ( k on) of the G protein to the agonist β2AR complex is directly correlated with ligand efficacy. These data support a model in which higher-efficacy agonists induce the β2AR to adopt a conformation that is more likely to recruit G protein. Conversely, these data did not support the role of agonist binding kinetics in determining the molecular basis of efficacy.
Journal Article
Evolution of Population Structure in a Highly Social Top Predator, the Killer Whale
Intraspecific resource partitioning and social affiliations both have the potential to structure populations, though it is rarely possible to directly assess the impact of these mechanisms on genetic diversity and population divergence. Here, we address this for killer whales (Orcinus orca), which specialize on prey species and hunting strategy and have long-term social affiliations involving both males and females. We used genetic markers to assess the structure and demographic history of regional populations and test the hypothesis that known foraging specializations and matrifocal sociality contributed significantly to the evolution of population structure. We find genetic structure in sympatry between populations of foraging specialists (ecotypes) and evidence for isolation by distance within an ecotype. Fitting of an isolation with migration model suggested ongoing, low-level migration between regional populations (within and between ecotypes) and small effective sizes for extant local populations. The founding of local populations by matrifocal social groups was indicated by the pattern of fixed mtDNA haplotypes in regional populations. Simulations indicate that this occurred within the last 20,000 years (after the last glacial maximum). Our data indicate a key role for social and foraging behavior in the evolution of genetic structure among conspecific populations of the killer whale. [PUBLICATION ABSTRACT]
Journal Article
Fivefathers: Interviews with late Twentieth Century Scottish Poets
Five interview-based essays celebrating Sorley MacLean, Iain Crichton Smith, George Mackay Brown, Norman MacCaig and Edwin Morgan.
eBook
The Edinburgh Companion to Contemporary Scottish Poetry
The last three decades have seen unprecedented flourishing of creativity across the Scottish literary landscape, so that contemporary Scottish poetry constitutes an internationally renowned, award-winning body of work. At the heart of this has been the work of poets. As this poetry makes space for its own innovative concerns, it renegotiates the poetic inheritance of preceding generations. At the same time, Scottish poetry continues to be animated by writing from other places.
The Edinburgh Companion to Contemporary Scottish Poetryis the definitive guide to this flourishing poetic scene. Its chapters examine Scottish poetry in all three of the nation's languages. It analyses many thematic preoccupations: tradition and innovation; revolutions in gender; the importance of place; the aesthetic politics of devolution. These chapters are complemented by extended close readings of the work of key poets that have defined this era, including Edwin Morgan, Kathleen Jamie, Don Paterson, Aonghas MacNeacail and John Burnside.
Key Features
A thorough guide to contemporary Scottish poetry and poets, making the book an ideal course textReflects the ways in which the work of Scottish poets reflects a radical cultural independence following DevolutionProvides authoritative essays by the leading experts in the fieldIncludes a valuable synoptic bibliography
eBook
Agonist efficacy at the β 2 AR is driven by the faster association rate of the G s protein
The β
-adrenoceptor (β
AR) is a class A G protein-coupled receptor (GPCR). It is therapeutically relevant in asthma and chronic obstructive pulmonary disease (COPD), where β
AR agonists relieve bronchoconstriction. The β
AR is a prototypical GPCR for structural and biophysical studies. However, the molecular basis of agonist efficacy at the β
AR is not understood. We hypothesised that the kinetics of GPCR-G protein interactions could play a role in determining ligand efficacy. By studying a range of agonists with varying efficacy, we examined the relationship between ligand-induced mini-G
binding to the β
AR and ligand efficacy, along with the ability of individual ligands to activate the G protein in cells.
We used NanoBRET technology to measure ligand-induced binding of purified Venus-mini-G
to β
AR-nLuc in membrane preparations under both equilibrium and kinetic conditions. In addition, we examined the ability of these β
AR agonists to activate the heterotrimeric G
protein, measured using the G
-CASE protein biosensor in living cells. This assay detects a reduction in NanoBRET between the nano-luciferase (nLuc) donor on the Gα subunit and Venus acceptor on the Gγ upon G
protein activation.
The 12 β
AR agonists under study revealed a broad range of ligand potency and efficacy values in the cellular G
-CASE assays. Kinetic characterisation of mini-G
binding to the agonist β
AR complex revealed a strong correlation between ligand efficacy values (E
) and mini-G
affinity (
) and its association rate (
). In contrast, there was no correlation between ligand efficacy and reported ligand dissociation rates (or residence times).
The association rate (
) of the G protein to the agonist β
AR complex is directly correlated with ligand efficacy. These data support a model in which higher-efficacy agonists induce the β
AR to adopt a conformation that is more likely to recruit G protein. Conversely, these data did not support the role of agonist binding kinetics in determining the molecular basis of efficacy.
Journal Article
Delivering an essential and sustainable water plan for Sydney, Australia
The water supply for Sydney, which is the largest city in Australia, has been affected by variable climate patterns which include long periods of drought. Water resource needs for the future will be significantly affected by climate change and population growth. A ‘Water for Life’ equation has been adopted as a multi-faceted approach to achieving future, sustainable water security. The four parts of the equation are dams, recycling, water efficiency and desalination. Significant achievements have been made over the last 10 years which have allowed us to bolster the demand/supply balance by 50%. In the future, a portfolio approach will be used to select schemes for water supply security. Major factors considered will include construction and operational cost, volume of water saved or produced, public health and environmental risk, customer and community acceptance and political willpower.
Journal Article
Multiple intramolecular triggers converge to preferential G protein coupling in the CB 2 R
G protein-coupled receptors (GPCRs) are important therapeutic drug targets for a wide range of diseases. Upon activation, GPCRs can initiate several signaling pathways, each with unique therapeutic implications. Therefore, understanding how drugs selectively engage specific signaling pathways becomes paramount. However, achieving this selectivity remains highly challenging. To unravel the underlying multifaceted mechanisms, we integrate systematic mutagenesis of the CB
R, comprehensive profiling of G
and β-arrestin1 engagements and computer simulations to track the effects of mutations on receptor dynamics. Our research reveals multiple triggers within a complex allosteric communication network (ACN) that converge to preferential CB
R coupling by modulating evolutionarily conserved motifs. Utilizing network path analysis, we find that potent triggers are typically highly connected nodes and are located near regions of high information transmission within the ACN. Our insights highlight the complexity of GPCR signaling and provide a framework for the rational design of drug candidates tailored to evoke specific functional responses, ultimately enhancing the precision and efficacy of therapeutic interventions.
Journal Article