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October 2022 Increased Anxiety-like Behaviors in Adgra1-/- Male But Not Female Mice are Attributable potential role of ADGRA1 in the neurobehaviors of mice by comparing Adgra1-/- and their wild-type (wt) littermates male but not female mice exhibited elevated anxiety levels in the open field, elevated plus maze, and light-dark

October 2022 ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to found that nsSNPs rs35106420, rs61747658, and rs734644, previously reported to be associated and in linkage harbored in the ADGLR3-hormone receptor domain (HRM, a common extracellular domain of the secretin-like GIP has been linked to the pathogenesis of diabetes mellitus, and our analyses suggest a potential link showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure, most likely

sample preparation strategies, including expression and isolation of A2AAR and assembly of A2AAR in lipid

October 2022 Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case Ligands must first partition into the surrounding membrane and take lipid paths to these sites. Remarkably, a significant part of the bound ligands appears exposed to the membrane lipids. to ligand access and binding is often overlooked and poorly understood. Using classical and enhanced molecular dynamics simulations, we show that membrane lipids are critical

Depending on which ligand activates a receptor, it can engage different intracellular transducers. Ligands eliciting biased signalling may constitute better drugs with higher efficacy and fewer adverse However, ligand bias is very complex, making reproducibility and description challenging. Here, we provide guidelines and terminology for any scientists to design and report ligand bias experiments receptor research and drug discovery communities continue to advance our understanding and exploitation of ligand

August 2022 "Fluorescently labeled ligands are versatile molecular tools to study G protein-coupled receptors Here, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric previously reported intracellular CCR2 antagonists, several tetramethylrhodamine (TAMRA)-labeled CCR2 ligands By means of these studies, we developed 14 as a fluorescent CCR2 ligand, enabling cell-free as well as Thus, our small-molecule-based fluorescent CCR2 ligand 14 represents a promising tool for future studies

Genetic variants in ITGA9, which encodes the α9 subunit of integrin α9β1, and SVEP1, a ligand for integrin

August 2022 "G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies Previous studies revealed how ligands with different efficacies activate GPCRs. Here, we investigate how a GPCR activates G-proteins upon binding ligands with different efficacies. effects on the cellular signaling from β1-AR to the cAMP response initiated by the three different ligands These data provide insights into the ligand efficacy in the activation of GPCRs and G-proteins."

A variety of ligands for CB1 receptors have been developed as promising drug candidates for the treatment receptor in different functional states have significantly improved our molecular understanding of CB1 ligand These advances have paved the way for development of novel ligands for different therapeutic applications review, we describe the structural determinants for modulation of CB1 receptors by different types of ligands LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane

August 2022 Production of human A 2A AR in lipid nanodiscs for 19 F-NMR and single-molecule fluorescence sample preparation strategies, including expression and isolation of A2AAR and assembly of A2AAR in lipid

September 2022 Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand To understand the basis of the ligand preferences of the receptors and to assist structure-based drug Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison

In summary, our study shows that inhibiting homodimerization has a setmelanotide-like effect on Gq/11

September 2022 A2B Adenosine Receptor Enhances Chemoresistance of Glioblastoma Stem-Like Cells under and the presence of a cell subpopulation that persists under hypoxic niches, called glioblastoma stem-like

September 2022 High GPER expression in triple-negative breast cancer is linked to pro-metastatic pathways significant correlation with the mRNA subtype of TNBC (P = 0.001), total metastatic events (P = 0.019) and liver Besides, high GPER expression was significantly linked to the worse survival in patients with lymph node Transcriptome-based bioinformatics analysis revealed that GPER was linked to pro-metastatic pathways

September 2022 "Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation

Furthermore, we found that certain GPCR ligands can regulate GPCR/14-3-3 signals temporally, suggesting

September 2022 Fly casting with ligand sliding and orientational selection supporting complex formation GA-mD-VcMD is a generalized ensemble method that produces a free-energy landscape of the ligand-receptor Last, in the pocket, ligand–receptor attractive native contacts are formed. Eventually, the native-like complex is completed. The ligand-sliding corresponds to overcoming of a free-energy barrier between the basins."

September 2022 "Class A (rhodopsin-like) G protein-coupled receptors (GPCRs) are constitutive phospholipid scramblases as evinced after their reconstitution into liposomes. We considered whether cholesterol, a prominent component of the plasma membrane, limits the ability of GPCRs to scramble lipids. This mechanism may explain the inability of GPCRs to scramble lipids at the plasma membrane."

ciliary membrane models, respectively, to study the interactions of SMO with cholesterol and other lipid Further detailed analysis of the dynamics of the TMD reveals the movements of TM5, TM6, and TM7, linked

September 2022 "The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an

central question of GPCR drug discovery is to understand what determines the agonism or antagonism of ligands Ligands exert their action via the interactions in the ligand binding pocket. We hypothesized that there is a common set of receptor interactions made by ligands of diverse structures We computationally docked ~2700 known β2AR ligands to multiple β2AR structures, generating ca 75 000 docking poses and predicted all atomic interactions between the receptor and the ligand.

Endogenous ligands, named endocannabinoids, are produced “on demand” to finely regulate the synthesis It is well known that immune challenges, such as exposure to lipopolysaccharide, the main component of

receptors (aGPCRs) are cell-surface proteins with large extracellular regions that bind to multiple ligands structure revealed that the LK30 binding site on ADGRL3 overlaps with the binding site for an ADGRL3 ligand specifically broke the trans-cellular interaction of ADGRL3 with teneurin, but not with another ADGRL3 ligand Our work provides proof of concept for the modulation of isoform- and ligand specific aGPCR functions

Corporation (“Sosei Heptares”; TSE: 4565) today announces that in connection with the Collaboration and License Agreement (“License Agreement”) with Neurocrine Biosciences, Inc. As such, the License Agreement became effective on 22 December 2021. With completion of the applicable waiting period under the HSR Act, under the terms of the License Agreement

The answer lies in a misunderstood property called efficacy—the power of a drug to trigger a response

C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C chemokine motif receptor 4 (CXCR4) We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as The development of more selective ACKR3 ligands should allow us to better appreciate the unique roles In this study, novel selective ligands for ACKR3 were discovered and the site of interactions between

Therefore, S1R ligands possess a variety of potential clinical applications with a great interest in Upon optimization, this series of compounds could represent potential clinically useful S1R ligands for

Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies for such ligands

Ligands bounce in and out of receptor sites, competing dynamically. how your ligand’s presence reshapes the ensemble. A high-affinity ligand often has higher efficacy, but the relationship is not linear. By stabilizing certain receptor states over others, ligands literally remodel the energy landscape. More nuanced control, fewer off-target liabilities, and novel therapeutic windows.

strategies that anticipate physiological resistance, to no-wash internalization detection tools, to HTRF ligand Breakthroughs this week: Lilly to build $5B manufacturing facility in Virginia; Novo Nordisk flags drug It’s a response to unmet scientific needs: Replace microscopy-heavy workflows with no-wash, live-cell GPCR Podcast, the Revvity team built pHSense™ from the ground up by listening to what GPCR scientists to the podcast ➤ Celtarys Research – Optimizing HTRF with Fluorescent Ligands Traditional ligand-binding