October 2022 Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment prescription of traditional Chinese Medicine (TCM), is widely used in the treatment of depression, but its mechanism pharmacology method was used to constructe the "herb-component-target" network, and elucidated KXS potential mechanisms Go enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the

September 2022 "Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric IUPHAR Review 34 "Functional advances have guided our knowledge of physiological and fatal pathological mechanisms dynamics of AngII receptors and how structural knowledge can be transformative in understanding the mechanisms

Moreover, the mechanisms underlying regulation of TRPM3 are largely unexplored.

November 2022 Deciphering the signaling mechanisms of β-arrestin1 and β-arrestin2 in regulation of cancer overview of the role of β-arrestins with a primary emphasis on the signaling processes which underlie the mechanism

October 2022 "While the role of G-protein-coupled receptors (GPCR) in cancer is acknowledged, their underlying signaling pathways are understudied. Protease-activated receptors (PAR), a subgroup of GPCRs, form a family of four members (PAR1-4) centrally involved in epithelial malignancies. PAR4 emerges as a potent oncogene, capable of inducing tumor generation. Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical for colon cancer growth. In addition to PH-Akt/PKB association, other PH-containing signal proteins such as Gab1 and Sos1 also associate with PAR4. Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate these associations. Pc(4-4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding motifs. It effectively attenuates PAR2&4-Akt/PKB associations; PAR4 instigated Matrigel invasion and migration in vitro and tumor development in vivo. EGFR/erbB is among the most prominent cancer targets. AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively inhibited by Pc(4-4). The presence of PAR2 and PAR4 in biopsies of aggressive breast and colon cancer tissue specimens is demonstrated. We propose that Pc(4-4) may serve as a powerful drug not only toward PAR-expressing tumors but also for treating EGFR/erbB-expressing tumors in cases of resistance to traditional therapies. Overall, our studies are expected to allocate new targets for cancer therapy. Pc(4-4) may become a promising candidate for future therapeutic cancer treatment." Read more at the source #DrGPCR #GPCR #IndustryNews

October 2022 Mechanism of enhanced sensitivity of mutated β-adrenergic-like octopamine receptor to amitraz However, the underlying molecular mechanism of the enhanced sensitivity or toxicity of amitraz to mutated Here, molecular dynamics simulations are employed to explore the implied mechanism of the enhanced sensitivity

August 2022 Deciphering the signaling mechanisms of β-arrestin1 and β-arrestin2 in regulation of cancer overview of the role of β-arrestins with a primary emphasis on the signaling processes which underlie the mechanism

September 2022 To probe the activation mechanism of the Delta opioid receptor by an agonist ADL5859 started crystal structures of the DOR with both agonist and antagonist have recently been solved, the activation mechanism and multiple microsecond molecular dynamic (MD) simulations were conducted to probe the activation mechanism

Due to its irreversible activation mechanism, some agonists that rapidly desensitized PAR2 have been

injection of its ligand, 7α,25-dihydroxycholesterol (7α,25-OHC), causes time-dependent development of mechano-and However, the molecular mechanisms engaged downstream of GPR183 in the spinal cord are not known. In support, we found that the development of 7α,25-OHC/GPR183-induced mechano-allodynia was associated SIGNIFICANCE STATEMENT: Using a multi-disciplinary approach, we have characterized the molecular mechanisms

Adhesion of GPCR EMR2/ ADGRE2 to Circulating Neutrophils Is Not Related to Injury Severity Unveiling Mechanical Activation: GAIN Domain Unfolding and Dissociation in Adhesion GPCRs Molecular sensing of mechano- and and Signaling GPR101: Modeling a constitutively active receptor linked to X-linked acrogigantism The mechanism altered by the tumor microenvironment High Metabolite Concentrations in Portal Venous Blood as a Possible Mechanism outbreaks in Pakistan Structural and Molecular Insights into GPCR Function Structural and signaling mechanisms

explored how growth factors can modulate canonical G protein signaling, shedding light on molecular mechanisms Mechanisms of Inhibition: The study identified three distinct mechanisms by which phosphorylation inhibits modulate G protein signaling through specific phosphorylation events highlights a nuanced regulatory mechanism In conclusion, this research elucidates the molecular mechanisms by which growth factors influence G

MC3R) is a G-protein coupled receptor (GPCR) that is defined as a regulator of appetite/hunger balance mechanisms In addition to its function about weight gain and appetite control mechanisms of MC3R, recent studies Despite the drastic effects of the MC3R deficiency in humans and other mammals, its cellular mechanisms control of growth, puberty, and circadian rhythm, and, 3) its protein-protein interactions and cellular mechanisms

Activation of signaling effectors by G-protein coupled receptors (GPCRs) depends on different molecular mechanisms Although studies have focused on the G-protein signaling state, the mechanism for β-arrestin signaling conformational changes in response to biased ligands and could therefore participate in a molecular mechanism

However, little is known about the mechanism for GP coupling and activation for class C GPCRs. Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces This mechanism provides fresh insights into the mechanistic details of class C GPCRs activation expected

thought, and have the activation of serotonin (5-HT) 2A receptors (5-HT2A Rs) as a main pharmacological mechanism In particular, focus lies on the mechanism behind the techniques, and the specific advantages and challenges attempting to compare functional outcomes from different studies, both linked to the specific assay mechanism

With continued study of their function and mechanism of action, there is a greater understanding of how and their downstream effectors, there is increasing appreciation for the elegance of the regulatory mechanisms

Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation.

internalized activation" provides a completely new understanding for the receptor internalization, the mechanism postinternalization fates, and related diseases, which will offer new insights into the regulatory mechanism

dipping of the cleaved stalk peptide into the ligand-binding pocket of receptors; however, the detailed mechanism The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms

The resolution of these Cryo-EM structures provided the basis for the mechanism of self-activation of Last month a very detailed paper analyzed the molecular mechanisms of the aGPCRs self-activation as well This paper proposes a series of molecular mechanisms that would be occurring during the self-activation Barros-Álvarez, X., et al., The tethered peptide activation mechanism of adhesion GPCRs. Xiao, P., et al., Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4.

essentials: Measuring the pharmacologic activity of ligands (affinity, efficacy, co-operativity) Determining mechanisms Multiplexed mapping of the interactome of GPCRs with receptor activity-modifying proteins Molecular mechanism pharmacology Industry News Muscarinic drugs breathe new life into schizophrenia pipeline GPCR Dynamics Reveal Mechanisms

therapeutic potential of autophagy‐enhancing agent, trehalose, or related sugar compounds, and the underlying mechanism The mechanisms underlying their anti‐inflammatory effects were assessed using specific inhibitor, genetic

of Pharmacology I October 3, 10, 17, 24 (four sessions) Topics: Pharmacologic activity measurement, mechanisms Microswitches Nuclear translocation of the membrane oxoeicosanoid/androgen receptor, OXER1: Possible mechanisms macrophages Structural and Molecular Insights into GPCR Function Insights into the structure and activation mechanism class B1 GPCR family members Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism

only from intricate receptor-G protein interactions but also from the influence of downstream effector mechanisms GPCR priming opens new avenues for understanding the nuanced regulatory mechanisms governing GPCR signalling Continued exploration into the molecular mechanisms underlying this phenomenon could unveil new dimensions

Therefore, it is imperative to understand the precise molecular mechanism of H2R biology. In this aspect, our present data shed new light on the unexplored H2R signaling mechanisms.

of Pharmacology I October 3, 10, 17, 24 (four sessions) Explore pharmacologic activity measurement, mechanisms protein-coupled receptor structural landscape: Major milestones and future directions Going rogue: mechanisms and Molecular Insights into GPCR Function Delineating the stepwise millisecond allosteric activation mechanism single-nucleotide variants modulates receptor processing and functional activity Differential pathogenetic mechanisms