A5033206899- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Protein Kinase Regulation and GTPase Signaling
- Diabetes Treatment and Management
- Cholesterol and Lipid Metabolism
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Asthma and respiratory diseases
- Pancreatic function and diabetes
- Caveolin-1 and cellular processes
- Neuroscience and Neuropharmacology Research
- Machine Learning in Bioinformatics
- Nicotinic Acetylcholine Receptors Study
- Drug Transport and Resistance Mechanisms
- Retinal Development and Disorders
University of Copenhagen
2019-2025
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2023
Scripps (United States)
2023
Scripps Research Institute
2019-2021
Monash University
2016-2018
The glucagon‐like peptide‐1 receptor (GLP‐1R) plays an important role in regulating insulin secretion and reducing body weight, making it a prominent target the treatment of type 2 diabetes obesity. Extensive research on GLP‐1R signaling has provided insights into connection between function physiological outcomes, such as correlation Gs secretion, yet exact mechanisms remain unclear. Here, we explore internalization pathway GLP‐1R, which is crucial for controlling release maintaining...
Significance Chemical diversity has recently risen as key structural feature for the discovery of novel selective drugs G protein-coupled receptors (GPCRs). However, traditional drug technique combinatorial chemistry coupled to high-throughput screening become less attractive because its immense financial impact. To address this problem, we implemented a computer-aided design approach, using M 2 muscarinic acetylcholine receptor (mAChR) GPCR model, and performed computational enhanced...
G protein-coupled receptors (GPCRs) convert extracellular stimuli into intracellular signaling by coupling to heterotrimeric proteins of four classes: Gi/o, Gq, Gs, and G12/13. However, our understanding the protein selectivity GPCRs is incomplete. Here, we quantitatively measure enzymatic activity in living cells reveal 124 with exact rank order their preference. Using this information, establish a classification functional selectivity, discover existence G12/13-coupled receptor,...
Significance The orthosteric binding sites of the five muscarinic acetylcholine receptor (mAChR) subtypes are highly conserved, making development selective antagonists challenging. allosteric these receptors more variable, allowing one to imagine modulators that confer subtype selectivity, which would reduce major off-target effects antagonists. Accordingly, a large library docking campaign was prosecuted seeking unique positive (PAMs) for antagonists, ultimately revealing PAM substantially...
The chemotactic G protein–coupled receptor GPR183 and its most potent endogenous oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-OHC) are important for immune cell positioning in secondary lymphoid tissues. This receptor-ligand pair is associated with various diseases, some cases contributing favorably other adversely, making an attractive target therapeutic intervention. We investigated the mechanisms underlying internalization role of main biological function receptor, chemotaxis. found...
G protein-coupled receptors (GPCRs) are seven transmembrane that respond to external stimuli and undergo conformational changes activate proteins modulate cellular processes leading biological outcomes. To prevent overstimulation prolonged exposure stimuli, GPCRs regulated by internalization. While the canonical GPCR internalization mechanism in mammalian cells is arrestin-dependent, clathrin-mediated endocytosis, more diverse mechanisms have been described over years. However, there a lack...
Abstract The GPR15 receptor is a G protein‐coupled (GPCR), which activated by an endogenous peptide GPR15L(25–81) and C‐terminal fragment GPR15L(71–81). signals through the i/o pathway to decrease intracellular cyclic adenosine 3′,5′‐monophosphate (cAMP). However, activation profiles of within subtypes have not been examined. Moreover, whether can also couple s , q/11 12/13 unclear. Here, GPR15L(71–81) are used as pharmacological tool compounds delineate receptor‐mediated Gα protein...
Muscarinic acetylcholine receptors (mAChRs) are exemplar models for understanding G protein–coupled receptor (GPCR) allostery, possessing a "common" allosteric site in an extracellular vestibule (ECV) synthetic modulators including gallamine, strychnine, and brucine. In addition, there is intriguing evidence of endogenous peptides/proteins that may target this region at the M<sub>2</sub> mAChR. A common feature mAChR negative (NAMs) their cationic nature. Using structure-based approach, we...
GPR15 is a G protein-coupled receptor involved in immune disorders such as human immunodeficiency virus-induced enteropathy, multiple sclerosis, and colitis. Yet, the important endocytosis mechanism of remained unclear. This study determined participation endocytic machinery proteins, including Gα kinases (GRKs), protein kinase C, arrestins, clathrin, caveolin, dynamin internalization. The results demonstrate that internalization moderately dependent on GRKs highly caveolin dynamin....
Allosteric binding sites on G protein-coupled receptor (GPCR) can be targeted by synthetic or natural (endogenous) molecules (van der Westhuizen et al., 2015). However, the (patho)physiological role(s) of many endogenous allosteric modulators remain poorly understood. One interesting example is major basic protein (MBP), a highly peptide that acts as negative modulator (NAM) acetylcholine (ACh) at airway M2 muscarinic receptors (mAChR; Jacoby 1993). We hypothesized that, in addition to MBP,...
Allosteric binding sites on G protein-coupled receptor (GPCR) can be targeted by synthetic or natural (endogenous) molecules (van der Westhuizen et al., 2015). However, the (patho)physiological role(s) of many endogenous allosteric modulators remain poorly understood. One interesting example is major basic protein (MBP), a highly peptide that acts as negative modulator (NAM) acetylcholine (ACh) at airway M2 muscarinic receptors (mAChR; Jacoby 1993). We hypothesized that, in addition to MBP,...