However, how these states impact GPCRs biological function and therapeutic targeting remains incompletely

involves deliberately altering the DNA sequence of a gene to study the resulting changes in protein function understanding of how drugs interact with different receptor regions and link these interactions to functional This technique has uncovered fundamental aspects of the G protein-coupled receptor (GPCR) function, including Targeted mutagenesis may miss broader functional regions, while random mutagenesis generates extensive play a pivotal role in addressing these obstacles, enhancing our understanding of GPCR structure and function

Probing GPCR and β-Arrestin conformational states: methods and implications The formation of functional Nevertheless, the diverse functionalities of various GPCRs, coupled with the fluctuating expression of In addition, the question of whether β-arrestin1 and 2 serve overlapping or distinct functions remains Knockout studies in mice suggest that β-arrestin isoforms possess some level of functional redundancy The observed variations in β-arrestin expression likely impact the composition and function of GPCR-mediated

The recently determined structures of B2R have provided molecular insights into the functions and regulation In this review, we summarize the structure and function of B2R in relation to drug discovery and discuss future research directions to elucidate the remaining unknown functions of B2R dimerization."

These dimeric forms, which can either be transient or stable, are believed to influence the function GPCRs can form both homodimers and heterodimers, which may play a crucial role in modulating receptor function Such findings suggest that dimerization is critical for regulating GPCR function, particularly with respect GPCRs is an emerging area of research that has far-reaching implications for our understanding of GPCR function While class B1 GPCRs were initially thought to function primarily as monomers, mounting evidence suggests

In addition to its function about weight gain and appetite control mechanisms of MC3R, recent studies

However, it is unknown whether and how RAMP proteins may affect PTH1R function. Employing homology modeling, we describe the putative structural molecular basis underlying our functional activation and signaling of a GPCR that may provide a new venue for highly specific modulation of GPCR function

September 2022 Identification and functional characterization of the sulfakinin and sulfakinin receptor As a neuromodulator, it mediates a variety of behavioral processes and physiological functions in invertebrates However, there is no report on the functional role of SK in the Chinese white pine beetle, Dendroctonus

The aim of this work was to analyze the functional role of the specific arginine residue at position

August 2022 In vitro assays for the functional characterization of (psychedelic) substances at the serotonin to insufficiently described structure-activity relationships, hence illustrating the need for better functional Additionally, several variables are discussed that one should consider when attempting to compare functional

Here, we demonstrate a physical interaction between 5-HT2A and TrkB in vitro and in vivo using co-immunoprecipitation Our data reveal the functional role of 5-HT2A–TrkB receptor heterodimerization and suggest that the regulated expression of 5-HT2A and TrkB is a molecular mechanism for the brain-region-specific modulation of TrkB functions

October 2022 ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to However, the effect of ADGRL3 non-synonymous SNPs (nsSNPs) on the ADGRL3 protein function is vastly unknown Overall, the comprehensive application of bioinformatics tools showed that functional mutations in the

October 2022 GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches

November 2022 "Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs." Read more at the source #DrGPCR #GPCR #IndustryNews Subscribe to the Dr. GPCR Newsletter HERE

Thus, we investigated the regulatory functions of its β-adrenergic-like octopamine receptor (PxOctβ3) This study demonstrated the pharmacological properties and functions of PxOctβ3 in P. xylostella, thus

Electroretinography showed restoration of visual function in all three transgenic Gγ1-deficient lines Thus, while farnesylated Gγ subunits are functionally active and largely interchangeable in supporting

April 2022 "By Cliona MacSweeney | Apr 20, 2022 Cliona MacSweeney, a project director in our Translational Medicine department, recently presented this important pre-clinical work at SIRS2022 confirming the ability of the highly selective novel GPR52 agonist HTL00411718 to modulate centrally mediated locomotor activity in response to A2A receptor antagonists. This work highlights an important interplay between the adenosinergic and dopaminergic systems and suggests the potential for GPR52 agonists to control neuropsychiatric symptoms in conditions such as schizophrenia. " Read more at the source #DrGPCR #GPCR #IndustryNews

experimental structure of these receptors has yet to be determined, and key-residues controlling their function test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis and in vitro functional This combination of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular switches that encode agonist sensing and downstream signaling mechanisms within

September 2022 "The human sweet taste receptor is a heterodimeric receptor composed of two distinct G-protein-coupled receptors (GPCRs), TAS1R2 and TAS1R3. The TAS1R2 and TAS1R3 subunits are members of a small family of class C GPCRs whose members share the same architecture, comprising a Venus Flytrap (VFT) module linked to the seven transmembrane domains (TMDs) by a short cysteine-rich region (CRR). The VFT module of TAS1R2 contains the primary binding site for most of the sweet-tasting compounds, including natural sugars and artificial and natural sweeteners. However, cellular assays, molecular docking and site-directed mutagenesis studies have revealed that the VFT, CRR and TMD of TAS1R3 interact with some sweeteners, including the sweet-tasting protein brazzein. The aim of this study was to better understand the contribution of TAS1R2-VFT in the binding of sweet stimuli. To achieve this, we heterologously expressed human TAS1R2-VFT (hTAS1R2-VFT) in Escherichia coli . Circular dichroism spectroscopic studies revealed that hTAS1R2-VFT was properly folded with evidence of secondary structures. Using size-exclusion chromatography coupled with light scattering, we found that hTAS1R2-VFT behaves as a monomer. Ligand binding quantified by intrinsic tryptophan fluorescence showed that hTAS1R2-VFT is capable of binding sweet stimuli with Kd values, in agreement with physiological detection. Furthermore, we investigated whether the impact of point mutations, already shown to have deleterious effects on cellular assays, could impact the ability of hTAS1R2-VFT to bind sweet ligands. As expected, the ligand affinities of hTAS1R2-VFT were drastically reduced through the introduction of single amino acid substitutions (D278A and E382A) known to abolish the response of the full-length TAS1R2/TAS1R3 receptor. This study demonstrates the feasibility of producing milligram quantities of hTAS1R2-VFT to further characterize the mechanism of binding interaction and perform structural studies." Read more at the source #DrGPCR #GPCR #IndustryNews

July 2022 " Orion Biotechnology and Peptilogics are pursuing AI-driven drug discovery to explore new functional

September 2022 Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following

August 2022 G protein-coupled receptor kinase type 2 and β-arrestin2: Key players in immune cell functions This review summarizes the roles of GRK2/β-arrestin2 in immune cell function and focuses on the pathological

discuss both the ‘friend’ and ‘foe’ features of TGR5 by summarizing its tumor-suppressing and oncogenic functions

pharmacology, biology, behavior, and neurophysiology "The awareness of the potential importance of functional physiological studies implying that bias toward or against D1-mediated β-arrestin either can improve or impair functional the importance of understanding the translatability of cell and animal models to have more precise functional

in the length of their extracellular N-termini by 31 amino acids, but detailed insights into their functional

neuron morphogenesis and shapes chemo- and mechanosensation-dependent behavior in C. elegans via a trans function However, there is evidence that Latrophilins in the nematode Caenorhabditis elegans can also function independently of their seven-transmembrane domain and C terminus (trans function). This trans function is physiologically relevant in copulation behavior. complementing canonical functions via G protein-mediated signaling.

, the most drugged class of proteins in the human body, are plentiful and vary in utility, form and function

September 2022 "The follicle-stimulating hormone receptor (FSHR) belongs to the glycoprotein hormone receptors, a subfamily of G-protein-coupled receptors (GPCRs). FSHR is involved in reproductive processes such as gonadal development and maturation. Structurally, the extensive extracellular domain, which contains the hormone-binding site and is linked to the transmembrane domain by the hinge region (HR), is characteristic for these receptors. How this HR is involved in hormone binding and signal transduction is still an open question. We combined in vitro and in situ chemical crosslinking, disulfide pattern analysis, and mutation data with molecular modeling to generate experimentally driven full-length models. These models provide insights into the interface, important side-chain interactions, and activation mechanism. The interface indicates a strong involvement of the connecting loop. A major rearrangement of the HR seems implausible due to the tight arrangement and fixation by disulfide bonds. The models are expected to allow for testable hypotheses about signal transduction and drug development for GPHRs." Read more at the source #DrGPCR #GPCR #IndustryNews