Consider G-protein-coupled receptors-an expansive class of transmembrane signaling proteins that participate While early evidence for the role of oligomerization in receptor signaling came from ensemble biochemical for these techniques to advance our understanding of the role of oligomerization in G-protein-coupled receptor

Considering the central role of the serotonin 5-HT2A receptor in the distinct effects of psychedelics

architectures require multi-target engagement in the first place, and the therapeutic contexts where single-receptor co-administration cannot achieve How amino acid substitution within incretin peptide sequences shifts receptor selectivity across GLP-1, GIP, and glucagon receptor types The two-edged character of multi-target The compound is simultaneously a muscarinic receptor inhibitor and a cholinesterase inhibitor, two activities design strategies for building it into a single scaffold, and how peptide sequence modification shifts receptor

critical components of the intracellular signaling pathways that mediate the effects of G protein-coupled receptors For example, μ opioid receptor (MOR) interacts with Gαi/o and Gαz subunits, which have a slow enzymatic ; enhancing the activity of the G protein that is coupled to the receptor and leading to a decrease in Senese, N.B., et al., Regulator of G-Protein Signaling (RGS) Protein Modulation of Opioid Receptor Signaling Traynor, Differential modulation of mu- and delta-opioid receptor agonists by endogenous RGS4 protein

Orthosteric ligands preempt  natural signaling; they “take over” receptor behavior, forcing physiology Allosterics , in contrast, act more like tuning knobs—modulating receptor ensembles in partnership with The Dynamic Nature of Receptor Binding Forget the static “lock-and-key” metaphor. Ligands bounce in and out of receptor sites, competing dynamically. By stabilizing certain receptor states over others, ligands literally remodel the energy landscape.

CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin 1A Receptor "G protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins that transduce The serotonin1A receptor is a crucial neurotransmitter receptor in the GPCR family involved in a multitude In addition, we showed that membrane cholesterol stabilizes the serotonin1A receptor against thermal consensus (CRAC) motif in transmembrane helix 2 in conferring the thermal stability of the serotonin1A receptor

September 2022 "G-protein-coupled receptors (GPCRs) are involved in a wide array of physiological and Here, we find that protease-activated receptor 4 (PAR4) unexpectedly acts as a potent oncogene, inducing

October 2022 "Over three decades of research have provided thorough insights into G protein-coupled receptor Agonist activation of the β2-adrenoceptor (β2AR) causes its S-nitrosylation that is required for the receptor

Acquired hypocalciuric hypercalcemia (AHH) is a rare disease caused by calcium-sensing receptor (CaSR

GPCR Store, and a spotlight on the cryo-EM structure of the sweet taste receptor.   Ben Clements   In Episode 166, Ben Clements dives into opioid pharmacology, GPCR-targeted PAMs, and how Show off your receptor pride and support the mission. The official Dr. GPCR Store is live! A stunning cryo-EM structure of the sweet taste receptor (TAS1R2–TAS1R3) shows how aspartame and sucralose Biased signalling of Class B G protein-coupled receptor-targeted therapeutics .  

studies of AlphaFold, RoseTTAFold and Modeller: a case study involving the use of G-protein-coupled receptors G-protein-coupled receptor (GPCR) proteins are particularly interesting since they are involved in numerous

September 2022 "Melanocortin 4 receptor (MC4R) is part of the leptin-melanocortin pathway and plays an We have previously reported that the MC4R forms homodimers, affecting receptor Gs signaling properties protein–protein interaction were conducted, confirming decreased homodimerization capacities of chimeric receptors Gq/11 signaling of chimeric receptors was analyzed using luciferase-based reporter gene (NFAT) assays that inhibiting homodimerization has a setmelanotide-like effect on Gq/11 signaling, with chimeric receptors

intracellular allosteric binding site (IABS) has recently been identified at several G protein-coupled receptors Starting from vercirnon, an intracellular C-C chemokine receptor type 9 (CCR9) antagonist and previous

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular Different agonists can promote differential receptor-induced signaling responses - termed bias - potentially Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based to avoid differences in receptor phosphorylation influencing arrestin recruitment.

Divergence, however, in the amino acid sequences of rodent and human PTH receptors (rat and mouse PTH1Rs are 91% identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies

the actions of hormones, neurotransmitters and other signaling molecules that bind G-protein coupled receptors

as a potential target in colorectal cancer using novel fluorescent GPCR ligands "G-protein coupled receptors We selected the adenosine receptor 2B (A2BAR), specifically expressed in cancer cell lines compared with Fluorescent probes allowed semi-quantitative receptor mapping in living cells and validated the specific As well, fluorescent ligands were effective at monitoring real-time A2BAR receptor labeling using live-imaging

August 2022 "The apelin receptor (APJ) is a target for cardiovascular indications.

August 2022 "Background and purpose: Misuse of opioids has greatly affected our society. One potential solution is to develop analgesics that act at targets other than opioid receptors. These can be used either as stand-alone therapeutics or to improve the safety profile of opioid drugs Previous research showed that activation of Gq/11 proteins by G-protein coupled receptors has pro-nociceptive

October 2022 "Biased G protein-coupled receptor (GPCR) ligands, which preferentially activate G protein

October 2022 "The role of different G protein-coupled receptors (GPCRs) in the cardiovascular system 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. associated signaling machinery are localized in these cells with an emphasis on nuclear membrane-localized receptors

September 2022 "GPCRs are the most potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based anti-cancer drug is not fully investigated. Herein, we identified GPR108, a GPCR protein described in innate immune system, is a potential therapeutic target of cancer. Depletion of GPR108 dramatically inhibited the survival of various cancers. Notably, TNFα activation of NF-κB was totally impaired after GPR108 knockout. We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. Importantly, GA engaged with GPR108 and promoted its degradation, knockout of GPR108 remarkably blocked GA inhibition of NF-κB signaling. Furthermore, in vitro and in vivo assays demonstrated that GA was dependent on GPR108 to exert anti-cancer activity. Overall, our findings supported GPR108 as a promising therapeutic target of cancer, and provided a small molecule inhibitor GA directly and selectively targeting GPR108 for cancer therapy." Read more at the source #DrGPCR #GPCR #IndustryNews

Angiotensin 1-7 (Ang-1-7), an endogenous peptide, acts at the G protein coupled MAS1 receptors (MASR)

current understanding on how endogenous PTHrP transduces signals through its cognate G-protein coupled receptor (GPCR), the PTH type 1 receptor (PTHR), is largely derived from studies done with its N-terminal fragment demonstrate using various fluorescence imaging approaches at the single cell level to measure kinetics of (i) receptor activation, (ii) receptor signaling via Gs and Gq, and (iii) receptor internalization and recycling

their research on Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors Calebiro, Michael Decker, et al. for their study on Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors fibrosis progression Methods & Updates in GPCR Research Design, Synthesis, and Characterization of New δ Opioid Receptor-Selective Fluorescent Probes and Applications in Single-Molecule Microscopy of Wild-Type Receptors

Characterization of a new WHIM syndrome mutant reveals mechanistic differences in regulation of the chemokine receptor gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine receptor Interestingly, there were also significant differences in receptor degradation, with S339fs5 having a

2022 GPCRs steer G i and G s selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors

Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97 "Adhesion G-protein-coupled receptors (aGPCRs)-a major family of GPCRs-play critical roles in The orphan receptor GPR97, activated by glucocorticoid stress hormones, is a prototypical aGPCR.

September 2022 "GPCR signaling and function depend on their associated proteins and subcellular locations. Besides G-proteins and β-arrestins, 14-3-3 proteins participate in GPCR trafficking and signaling, and they connect a large number of diverse proteins to form signaling networks. Multiple 14-3-3 isoforms exist, and a GPCR can differentially interact with different 14-3-3 isoforms in response to agonist treatment. We found that some agonist-induced GPCR/14-3-3 signal intensities can rapidly decrease. We confirmed that this phenomenon of rapidly decreasing agonist-induced GPCR/14-3-3 signal intensity could also be paralleled with GPCR/β-arrestin-2 signals, indicating diminished levels of GPCR/signal adaptor complexes during endocytosis. The temporal signals could implicate either GPCR/14-3-3 complex dissociation or the complex undergoing a degradation process. Furthermore, we found that certain GPCR ligands can regulate GPCR/14-3-3 signals temporally, suggesting a new approach for GPCR drug development by modulating GPCR/14-3-3 signals temporally." Read more at the source #DrGPCR #GPCR #IndustryNews

  📚 This week’s paper highlights: GLP-1R/GIPR biased agonism enhances metabolic outcomes Ghrelin receptor Constitutive ghrelin receptor activity, not dimerization or ligand binding —reverses dopamine D2 signaling A MOR-positive allosteric modulator (BMS-986122) selectively enhances opioid signaling  through specific