A5054085362- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Diabetes Treatment and Management
- Neuroendocrine regulation and behavior
- Pharmacological Receptor Mechanisms and Effects
- Monoclonal and Polyclonal Antibodies Research
- Water Systems and Optimization
- Peptidase Inhibition and Analysis
- Water Treatment and Disinfection
- Groundwater flow and contamination studies
- Lipid Membrane Structure and Behavior
- Neutrino Physics Research
- Chemical Synthesis and Analysis
- Circadian rhythm and melatonin
- Atomic and Subatomic Physics Research
- Computational Drug Discovery Methods
- Hormonal Regulation and Hypertension
- Protein Kinase Regulation and GTPase Signaling
- Glycosylation and Glycoproteins Research
- Protein Structure and Dynamics
- Astrophysics and Cosmic Phenomena
- Pancreatic function and diabetes
- Immunodeficiency and Autoimmune Disorders
- Asthma and respiratory diseases
- Blood groups and transfusion
University of Oxford
2024-2025
Aston University
2016-2025
Coventry University
2018-2020
Monash University
2009-2015
Mayo Clinic in Arizona
2015
University of Essex
2015
University of Bristol
2013-2014
University of St. Thomas - Texas
2014
Australian Regenerative Medicine Institute
2012
University of Birmingham
2000-2010
Recently, the concept of ligand-directed signaling—the ability different ligands an individual receptor to promote distinct patterns cellular response—has gained much traction in field drug discovery, with potential sculpt biological response favor therapeutically beneficial signaling pathways over those leading harmful effects. However, there is limited understanding mechanistic basis underlying biased signaling. The glucagon-like peptide-1 a major target for treatment type-2 diabetes and...
The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and major therapeutic target for treatment diabetes. However, GLP-1 function complex, with multiple endogenous peptides that can interact the receptor, including full-length (1–37) truncated (7–37) forms each exist in an amidated form related peptide oxyntomodulin. We have investigated two allosteric modulators, Novo Nordisk compound 2 (6,7-dichloro2-methylsulfonyl-3-<i>tert</i>-butylaminoquinoxaline)...
Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to exploitation is an understanding events coupling ligand binding intracellular signaling. Activation class B G protein-coupled receptors driven by interaction peptide N terminus receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation effects on pathway-specific signaling from those modify...
The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and major therapeutic target for the treatment type II diabetes. However, regulation GLP-1R function complex with multiple endogenous peptides that interact receptor, including full-length (1–37) truncated (7–37) forms GLP-1 can exist in an amidated form (GLP-1(1–36)NH<sub>2</sub> GLP-1(7–36)NH<sub>2</sub>) related peptide oxyntomodulin. In addition, possesses exogenous agonists, exendin-4,...
The glucagon-like peptide 1 receptor (GLP-1R) is a promising target for the treatment of type II diabetes mellitus because its role in metabolic homeostasis. In recent years, difficulties with therapies have driven search small-molecule compounds to modulate activity this receptor. We recently identified quercetin, naturally occurring flavonoid, as probe-dependent, pathway-selective allosteric modulator GLP-1R-mediated signaling. Using Chinese hamster ovary cells expressing human GLP-1R, we...
The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled (GPCR) that key target for treatments type II diabetes and obesity. This receptor, like other GPCRs, displays biased agonism, though the physiologic significance of this yet to be elucidated. Previous work has implicated R2.60<sup>190</sup>, N3.43<sup>240</sup>, Q7.49<sup>394</sup>, H6.52<sup>363</sup> as residues involved in peptide-mediated with Q7.49<sup>394</sup> predicted form polar interaction network. In...
Abstract G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical protein signalling transmitted through conformational changes, also interact with other proteins. These include receptors, and channels, regulatory receptor-modifying proteins, notably receptor activity-modifying (RAMPs). RAMPs have at least 11 partners, including many class B receptors. Prototypic is the...
The class B G protein-coupled receptor (GPCR) calcitonin (CTR) is a drug target for osteoporosis and diabetes. N-glycosylation of asparagine 130 in its extracellular domain (ECD) enhances hormone affinity with the proximal GlcNAc residue mediating this effect through an unknown mechanism. Here, we present two crystal structures salmon calcitonin-bound, GlcNAc-bearing CTR ECD at 1.78 2.85 Å resolutions analyze mechanism glycan effect. N130 does not contact hormone. Surprisingly, are nearly...
Abstract The SNO $$+$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mo>+</mml:mo> </mml:math> collaboration reports its first spectral analysis of long-baseline reactor antineutrino oscillation using 114 tonne-years data. Fitting the neutrino probability to observed energy spectrum yields constraints on mass-squared difference $$\Delta m^2_{21}$$ <mml:mrow> <mml:mi>Δ</mml:mi> <mml:msubsup> <mml:mi>m</mml:mi> <mml:mn>21</mml:mn> <mml:mn>2</mml:mn> </mml:msubsup> </mml:mrow>...
A number of computer packages have been developed for modeling chlorine decay in water distribution networks. However, there is uncertainty as to the kinetic model that they should use mechanism. This paper explores performance six different models free over 200 bulk samples from a sources. The also presents results surveying longitudinal profile two situ pipe stretches. It concludes that, network purposes, it generally reasonable assume first-order kinetics and overall decay.
A number of computer packages have been developed for modeling chlorine decay in water distribution networks. However, there is uncertainty as to the kinetic model that they should use mechanism. This paper explores performance six different models free over 200 bulk samples from a sources. The also presents results surveying longitudinal profile two \Iin situ\N pipe stretches. It concludes network purposes, it generally reasonable assume first-order kinetics and overall decay.
Calcitonin receptor like-receptor is a family B G-protein coupled (GPCR). It requires activity modifying protein (RAMP) 1 to give calcitonin gene-related peptide (CGRP) receptor. Little known of how members this function. Proline residues often form important kinks in α-helices. Therefore, all proline within the transmembrane helices (Pro241, Pro244 helix 4, Pro275 5, Pro321 and Pro331 6) were mutated alanine. Pro241, Pro275, are highly conserved throughout GPCRs. The binding CGRP its...
The three receptor activity-modifying proteins (RAMPs) have been recognized as being important for the trafficking and function of a subset family B G protein-coupled receptors, although structural basis this has not well established. In current work, we use morphological fluorescence techniques, bioluminescence resonance energy transfer, bimolecular complementation to demonstrate that secretin associates specifically with RAMP3, but RAMP1 or RAMP2. We truncation constructs, peptide...
We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion V205 in G protein-coupled receptor, Calcitonin Receptor-Like Receptor (h
The adenosine 2A receptor (A2AR), a G-protein-coupled (GPCR), was solubilised and purified encapsulated in styrene maleic acid lipid particles (SMALPs). A2AR-SMALP associated with phospholipids characteristic of the plasma membrane Pichia pastoris, host used for its expression, confirming that native lipids. fluorescence spectrum showed broad emission peak at 330 nm, produced by endogenous Trp residues. inverse agonist ZM241385 caused 30% increase emission, unusually accompanied red-shift...
The glucagon-like peptide-1 receptor (GLP-1R) is a prototypical family B G protein-coupled that exhibits physiologically important pleiotropic coupling and ligand-dependent signal bias. In our accompanying article (Koole, C., Wootten, D., Simms, J., Miller, L. Christopoulos, A., Sexton, P. M. (2012) J. Biol. Chem. 287, 3642-3658), we demonstrate, through alanine-scanning mutagenesis, key role for extracellular loop (ECL) 2 of the in propagating activation transition mediated by GLP-1...