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

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

Self-docking and cross-docking simulations of G protein-coupled receptor-ligand complexes: Impact of ligand type and receptor activation state G protein-coupled receptors (GPCR) are the largest family of Ligand discovery aimed at identification of chemical tools and drug leads is aided by molecular docking Likewise, the relative importance of receptor activation state and ligand function differences have also after ligand placement.

stabilizes G-protein-coupled receptors (GPCR) in a fully active state and modulates their affinity for bound ligands we investigate the conformational changes induced by the binding of a nanobody (Nb80) on the active-like conformation of the receptor, independent of ligand binding, in contrast to the conditions under which Besides, ligand-specific subtle differences in the conformations assumed by intracellular loop 2 and extracellular loop 2 are captured from the trajectories of various ligand-bound receptors in the presence

We first synthesized a fluorescent ligand enabling equilibrium and kinetic binding studies via NanoBRET Applying this molecular tool in a membrane-based setup and in living cells, we discovered a 4-aminopyrimidine

Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their

Humanity has always sought to live longer and for this, multiple strategies have been tried with varying In this sense, G protein-coupled receptors (GPCRs) may be a good option to try to prolong our life while this way, we present the analysis of a series of GPCRs whose activity has been shown to affect the lifespan Our compilation of data revealed that the mechanisms most involved in the role of GPCRs in lifespan are antagonist drugs, depending on the beneficial or harmful effects of each GPCR, in order to prolong people's lifespan

Crystal structures suggest ligand access to the orthosteric binding site of MT1 and MT2 receptors through We investigated the feasibility of this lipophilic entry route for 2-iodomelatonin, a nonselective agonist significantly different in the two receptor subtypes, as assessed by metadynamics simulations, and during ligand melatonin receptor ligands. pocket on the surface of MT1 receptor, which could participate in the recognition of MT1-selective ligands

October 2022 "The role of different G protein-coupled receptors (GPCRs) in the cardiovascular system is well understood in cardiomyocytes and vascular smooth muscle cells (VSMCs). In the former, stimulation of Gs-coupled receptors leads to increases in contractility, whereas stimulation of Gq-coupled receptors modulates cellular survival and hypertrophic responses. In VSMCs, stimulation of GPCRs also modulates contractile and cell growth phenotypes. Here, we will focus on the relatively less well-studied effects of GPCRs in cardiac fibroblasts, focusing on key signaling events involved in the activation and differentiation of these cells. We also review the hierarchy of signaling events driving the fibrotic response and the communications between fibroblasts and other cells in the heart. We discuss how such events may be distinct depending on where the GPCRs and their associated signaling machinery are localized in these cells with an emphasis on nuclear membrane-localized receptors. Finally, we explore what such connections between the cell surface and nuclear GPCR signaling might mean for cardiac fibrosis." Read more at the source #DrGPCR #GPCR #IndustryNews

November 2021 "Target class-specific libraries mean you need to screen less to identify high-quality Antibody developers are increasingly utilising antibody libraries to derive high-quality, drug-like biologics As a result, most approved library-derived antibodies originate from just three libraries. To target hard-to-drug targets like G protein-coupled receptors (GPCRs), more libraries, including better and more targeted libraries, are needed."

January 2022 "G-protein-coupled receptors’ star has been on the rise in biotech in recent years as researchers have discovered the vast potential for GPCR-targeting drugs in treating a range of health conditions, from cancer and genetic disorders to inflammation and metabolic imbalances. Among those hitching their wagons to that star are Verily and Sosei Heptares, which have struck a research agreement to discover new GPCR targets that’ll fuel the development of potential drug candidates. The financial details of the strategic collaboration weren’t released, but Sosei Heptares’ past two team-ups in GPCR-based drug discovery have clocked in at $1 billion—with Genentech—and, just last November, $2.6 billion in a partnership with Neurocrine." Read more at the source #DrGPCR #GPCR #IndustryNews

June 2022 "June 15, 2022 06:30 AM EDT - In 2016, Abbie Celniker was promoted to partner at Third Rock Ventures as the firm raised just over $600 million for its fourth fund. Since then, Celniker has helped usher in an additional fund and headed a few startups as interim CEO. Coming on its 15th year, Third Rock Ventures announced its sixth fund today — and largest one by far — at a whopping $1.1 billion. Adding it all up, Third Rock has raised $3.8 billion since its inception. That money has gone to some 60 biotechs, much of it as early funding." Read more at the source #DrGPCR #GPCR #IndustryNews

of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand

While traditional drug discovery programs have focused on the development of ligands targeting the binding site of endogenous ligands (orthosteric site), allosteric modulators offer new avenues for the regulation identification of multiple allosteric sites and significantly enhanced our understanding of how allosteric ligands systematic analysis of the currently available GPCR structures in complex with small-molecule allosteric ligands in terms of the location of allosteric pockets, receptor-ligand interactions, and the chemical features

2022 Identification of A2BAR as a potential target in colorectal cancer using novel fluorescent GPCR ligands We selected the adenosine receptor 2B (A2BAR), specifically expressed in cancer cell lines compared with stromal cells, to explore the use of fluorescent ligands that can be used for target visualization. expression of A2BAR in CRC cell lines. As well, fluorescent ligands were effective at monitoring real-time A2BAR receptor labeling using live-imaging

We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from

In particular, focus lies on the mechanism behind the techniques, and the specific advantages and challenges that one should consider when attempting to compare functional outcomes from different studies, both linked to the specific assay mechanism and linked to its specific execution, as these may heavily impact the