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August 2022 A new Kunitz-type snake toxin family associated with an original mode of interaction with We aimed to exploit other mamba venoms to enlarge the V2R-Kunitz peptide family and gain insight into the MQ1 molecular mode of action. Conclusions and implications: A new function and mode of action is associated with the Kunitz peptides

July 2022 Confo Therapeutics receives €1.7 million VLAIO grant for further research on GPCR modulators

insight straight to discovery-phase scientists and R&D strategists — without the noise, hype, or outdated models In this session, you’ll gain: ✅ Proven strategies  to balance in vitro vs. in vivo testing early — when Allosteric modulators and biased ligands aren’t exotic outliers—they’re increasingly common outcomes Biased antibodies and allosteric antibody modulators are no longer theoretical—they exist. Key Questions Answered in this AMA Session How early in vivo models sharpen go/no-go calls.

requires a tethered agonist-mediated activation mechanism "The mechanistic details of the tethered agonist mode ) that mediate stronger signaling in mouse versus human GPR116 and recapitulate these findings in a model

In the current report we present evidence of the modulation of PK2/PKR2 activity by anosmin 1, since cysteine-rich (CR) and the FnIII.1 domains could assist the WAP domain both in the binding to PKR2 and in the modulation

In this lesson, you’ll gain: A strategic view of how chemical scaffolds shape pharmacologic outcomes Extracts from plants, fungi, bacteria, and environmental microorganisms provided the first potent modulators This enables: Positive Allosteric Modulators (PAMs) — enhance natural signaling Negative Allosteric Modulators They offer high specificity , favorable safety , and unique mechanisms , including GPCR modulation through Subscribers gain weekly lectures led by Dr.

We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR

GPCR Podcast : From Personal Pain to Scientific Purpose: Alex Serafini’s Journey We sit down with Dr. Serafini’s early struggles with chronic pain sparked a career focused on innovating where pain management His work challenges outdated targets, explores overlooked roles of GPCRs and RGS proteins in pain, and seeks to redefine translational models for patient realities. Explore blind spots:  The underestimated role of GPCRs and RGS proteins in chronic pain mechanisms.

September 2022 β2-Adrenergic Receptor Expression and Intracellular Signaling in B Cells Are Highly Dynamic during Collagen-Induced Arthritis "The sympathetic nervous system (SNS) has either a pro-inflammatory or anti-inflammatory effect, depending on the stage of arthritis. In the past, treatment of arthritic B cells with a β2-adrenergic receptor (β2-ADR) agonist has been shown to attenuate arthritis. In this study, the expression and signaling of β2-ADR in B cells during collagen-induced arthritis (CIA) were investigated to provide an explanation of why only B cells from arthritic mice are able to improve CIA. Splenic B cells were isolated via magnetic-activated cell sorting (MACS). Adrenergic receptors on B cells and intracellular β2-ADR downstream molecules (G protein-coupled receptor kinase 2 (GRK-2), β-Arrestin 2, p38 MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and cAMP response element-binding protein (CREB)) were analyzed at different time points in naïve and arthritic B cells with and without stimulation of β2-ADR agonist terbutaline by flow cytometry. β2-ADR-expressing B cells increase during CIA without a change in receptor density. Moreover, we observed a profound downregulation of GRK-2 shortly after induction of arthritis and an increase in β-Arrestin 2 only at late stage of arthritis. The second messengers studied (p38, ERK1/2 and CREB) followed a biphasic course, characterized by a reduction at onset and an increase in established arthritis. Stimulation of CIA B cells with the β-ADR agonist terbutaline increased pp38 MAPK independent of the timepoint, while pERK1/2 and pCREB were enhanced only in the late phase of arthritis. The phosphorylation of p38 MAPK, ERK1/2 and CREB in the late phase of arthritis was associated with increased IL-10 produced by B10 cells. The change of β2-ADR expression and signaling during sustained inflammation might be an integral part of the switch from pro- to anti-inflammatory action of sympathetic mechanisms in late arthritis." Read more at the source #DrGPCR #GPCR #IndustryNews

Join us for the first virtual cafe talk to hear about the amazing work that Dr. Brian Arey is doing. https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe/ #gpcr #drgpcr #virtualcafe

In this session, you’ll gain: A clear conceptual map of Schild analysis and its origins. Slopes <1  may reveal allosteric modulation , where the antagonist binds at a secondary site. The model’s flexibility accommodates both agonism and antagonism as long as the analysis targets equilibrium Modern pharmacology has powerful modeling software, yet Schild analysis remains the litmus test for mechanism

Additionally, new studies reveal how phosphorylation barcodes shape arrestin engagement, a biased NTSR1 modulator targets pain without the need for opioids, and a real-time lipid probe tracks early signaling events Terry Kenakin, these five modules reveal how location bias, intracellular signaling, and ligand kinetics GRK-Specific Phosphorylation Barcodes Shape Arrestin Engagement with ACKR3   A β-Arrestin-2-Biased NTSR1 Modulator for Non-Addictive Pain Relief   A Cell-Permeable Fluorescent Probe Illuminates Early PI(4,5)P₂ Dynamics

Dysregulation of RGS proteins has been implicated in a range of diseases, including cardiovascular disease, pain Relating to pain, RGS4 in pain regulation is a topic of increasing interest because it has been identified as a key player in the modulation of nociception[7]. as a Potential Target for Pain Management. Avrampou, K., et al., RGS4 Maintains Chronic Pain Symptoms in Rodent Models.

2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation

leading to the development of drugs with superior efficacy and reduced side effects in heart disease, pain Our previous work demonstrated that GPR3-mediated β-arrestin signaling modulates amyloid-β (Aβ) generation Here, we generated a G protein-biased GPR3 mouse model to investigate the physiological and pathophysiological leads to a decrease in the area and compaction of amyloid plaques in the preclinical AppNL-G-F AD mouse model

Regulation of PLCβ Signaling by Gq-Coupled and μOpioid Receptors Opposes Opioid- Mediated Antinociception "Pain The current frontline approach for pain-management is the use of opioid analgesics. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation

that contains various adhesion-related domains and a highly-conserved GPCR-autoproteolysis-inducing (GAIN GPR125 (ADGRA3), an orphan adhesion GPCR, has been shown to modulate planar cell polarity in gastrulating The cleavage appears to occur at an atypical GPCR proteolysis site within the GAIN domain during an early

EGFR "Background Fentanyl is an opioid analgesic and is widely used in ovarian cancer patients for pain Xenograft mouse model was generated to investigate the in vivo efficacy of fentanyl.

Internal and external modulation factors of the orexin system (REVIEW). Multi-omics integration analysis of GPCRs in pan-cancer to uncover inter-omics relationships and potential Function Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain Structure-based pharmacophore modeling 2. Developing a novel framework for structure-based pharmacophore model generation and selection.

membrane of cells, they have easier access to the receptors than those that need to get into the cells to modulate The activation of these pathways regulates pain modulation, memory consolidation, motor coordination neuroprotective functions and is now being investigated for its role in Parkinson’s disease and neuropathic pain Of the traditional GPCRs, CBRs are gaining ground as potential therapeutic targets in several CNS diseases

Modules: October 31st : The Eyes to See- The Importance of Pharmacologic Assays. Strategy to Enhance Azobenzene-Based Photopharmacology GPCRs in Cardiology, Endocrinology, and Taste Rap1A Modulates disorders Predicting biological activity and design of 5-HT6 antagonists through assessment of ANN-QSAR models framework combining molecular image and protein structural representations identifies candidate drugs for pain structure of human class C orphan GPCR GPR179 involved in visual processing Reliability of AlphaFold2 Models

β-arrestin-1 revealed by 19F NMR spectroscopy Role of protease activated receptor 4 (PAR4) in mouse models protein and fat synthesis GPCRs in Neuroscience Targeting sensory neuron GPCRs for peripheral neuropathic pain Expression prevalence and dynamics of GPCR somatostatin receptors 2 and 3 as cancer biomarkers beyond NET: a paired A method for multiple-sequence-alignment-free protein structure prediction using a protein language model Reviews, GPCRs, and more Potential of olfactory neuroepithelial cells as a model to study schizophrenia

Activation and Signaling Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain GPCRs in Neuroscience DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal Activity Models of Key GPCR Families in the Central Nervous System: A Tool for Many Purposes. Structure-based pharmacophore modeling 1. Automated random pharmacophore model generation.

factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors Kinetic Model cells GPCR Binders, Drugs, and more Structure-based identification of a G protein-biased allosteric modulator ENDO 2024 Highlighting Therapeutic Potential of its GPCR Drug Discovery Platform GPCRs and Emotional Pain

in epithelial cells Profiling the proximal proteome of the activated μ-opioid receptor Computational modelling effects on mouse metabolism Mechanistic insights into sodium ion-mediated ligand binding affinity and modulation receptor Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain Awards Domain Therapeutics to Present Latest Data on DT-9045, a First-in-class Negative Allosteric Modulator of PAR2 for Immuno-oncology Crinetics Pharmaceuticals gets grant for patent granted for somatostatin modulators

in isolation—they respond to the system they’re in, often through opposing processes that you must model In this session, you’ll gain: ✅ A mental model you can trust  for predicting how GPCR ligands behave This section outlines the logic required to match preclinical models to patient physiology and avoid In this module, you’ll explore how some receptor–agonist complexes continue signaling from endosomes, Your molecule isn’t failing—your model might be too simple.

Biased agonists differentially modulate the receptor conformation ensembles in Angiotensin II type 1 Characterization of a novel positive allosteric modulator of the α1A-Adrenergic receptor. Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P2 Lipids. Identification of a potential structure-based GPCR drug for interstitial cystitis/bladder pain syndrome Evaluating GPCR modeling and docking strategies in the era of deep learning-based protein structure prediction

Tobias Langenhan for his papers to highlight suggestions GAIN Domain Unfolding in Adhesion GPCRs Molecular ADGRE2 to Circulating Neutrophils Is Not Related to Injury Severity Unveiling Mechanical Activation: GAIN sensing of mechano- and ligand-dependent adhesion GPCR dissociation GPCR Activation and Signaling GPR101: Modeling and more Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Methods & Updates in GPCR Research GproteinDb in 2024: new G protein-GPCR couplings, AlphaFold2-multimer models

protein-protein interactions; and also by the presence of the GPCR-Autoproteolysis INducing (GAIN) domain These crystal structures showed how the Stalk region, which is a short peptide released from the GAIN ADGRG2/GPR64, and ADGRG4/GPR112 were reported in their self-activating state, i.e. a unique activation model selectivity of G-protein coupling using a mouse ADGRL3 receptor without extracellular region as a study model7 Comparison between a predicted model of inactive receptor structure and self-activated Cryo-EM highlighted

SNARE protein complex in neurotransmitter release has been well characterized, the mechanisms that modulate , which can interact with different fusion proteins and also this different molecular codes will be modulated Since MOR receptor regulates pain perception and reward, the dysfunction in the MOR-SNARE complex interaction can lead to various neurological disorders, such as chronic pain and addiction.