Before the advent of AlphaFold, homology modeling was the most common method for predicting G protein-coupled Homology modeling relies on using the known structure of a homologous protein as a template to model For proteins with low sequence similarity to available templates, homology models tend to be less accurate targeting TAAR1, more than double that of the homology models. Ligand discovery from a dopamine D3 receptor homology model and crystal structure.

receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R), a class B GPCR and an important modulator activation of PTH1R and its downstream signaling, we describe here that RAMP2 acts as a specific allosteric modulator Moreover, RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, most notably increasing Employing homology modeling, we describe the putative structural molecular basis underlying our functional of RAMPs in the activation and signaling of a GPCR that may provide a new venue for highly specific modulation

The mouse cytomegalovirus G protein-coupled receptor homolog, M33, coordinates key features of in vivo Animal models of CMV provide insights into their role in viral fitness. All cytomegalovirus (CMV) genomes analysed to date possess GPCR homologs with phylogenetic evidence for The mouse CMV (MCMV) GPCR homolog, designated M33, is important for cell-associated virus spread and

We designed an integrative approach to improve comparative modeling of TAS2Rs. We constructed accurate homology models of human TAS2Rs. As a test case, we examined the accuracy of the TAS2R16 model with site-directed mutagenesis and in vitro

October 2022 Comparative studies of AlphaFold, RoseTTAFold and Modeller: a case study involving the use Although the overall accuracy of the two non-homology-based modeling methods, AlphaFold and RoseTTAFold for GPCRs with the most widely used template-based software-Modeller. If only looking at each program's top-scored structure, Modeller had the smallest average modeling RMSD 73 cases with the top-scored model, respectively, where no good templates were available for Modeller

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 models are expected to allow for testable hypotheses about signal transduction and drug development

September 2022 Dynamics of tumor-associated macrophages in a quantitative systems pharmacology model of immunotherapy in triple-negative breast cancer "Quantitative systems pharmacology (QSP) modeling is immuno-suppressive tumor microenvironment, we incorporated the dynamics of TAMs into our previously published QSP model We show that through proper calibration, the model captures the macrophage heterogeneity in the tumor

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics approach of combining the data derived from steered molecular dynamics simulations and the Bell-Evans model

molecular understanding of CB1 ligand interactions, selectivity, receptor activation and allosteric modulation In this review, we describe the structural determinants for modulation of CB1 receptors by different types of ligands, as well as the differences between CB1 and its homologous, the CB2 receptor.

Additionally, we detect a shortening of PC in PINK1-deficient human cellular and mouse models of familial Furthermore, in sPD models, the shortening of PC is accompanied by increased Sonic Hedgehog (SHH) signal

analysis of a series of GPCRs whose activity has been shown to affect the lifespan of animal and human models

We report that arrestin-3 modulates Fgr activity with a hallmark bell-shaped concentration-dependence interaction, we determined the crystal structure of the Fgr SH3 domain at 1.9 Å resolution and developed a model This model suggests that Fgr interacts with arrestin-3 at multiple sites and is consistent with the locations

October 2022 "Over three decades of research have provided thorough insights into G protein-coupled receptor (GPCR) regulation. In a recent issue of Molecular Cell, Fonseca et al. identified a previously overlooked desensitization mechanism. Agonist activation of the β2-adrenoceptor (β2AR) causes its S-nitrosylation that is required for the receptor to internalize and desensitize. Eliminating β2AR S-nitrosylation by mutation of C265 augments β2AR protein kinase A signaling, enables β2AR nitric oxide (NO) signaling, renders mice resistant to bronchoconstriction, and protects mice from allergen-induced asthma." Read more at the source #DrGPCR #GPCR #IndustryNews

to this report we did not know how different serotonin receptor subtypes which share high sequence homology Likewise, in this work the authors identify for the first time the specific amino acids that modulate

Biased pharmacological modulators provide potential therapeutic benefits, including greater pharmacodynamic Therefore, the identification of such modulators as drug candidates is highly desirable. The biased signaling modulation of non-GPCR receptors has yet to be exploited. The challenges and methods for the discovery of TLR4 biased modulators are also outlined. modulators for other non-GPCR receptors.

studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode

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. cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators

Although many cardiovascular GPCRs have been extensively studied as model receptors for decades, new As a result, there is an ongoing need to develop novel approaches to monitor and to modulate GPCR activation

August 2022 "Abstract Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related This introduces an element of uncertainty in the accuracy of rodent models for performing such preclinical To overcome this potential uncertainty, we used a homologous recombination-based knockin (KI) approach The resulting homozygous hPTH1R-KI (humanized) mice were healthy over at least 10 generations and showed

However, reorganization of the actin cytoskeleton upon modulation of membrane cholesterol and its consequences crucial neurotransmitter G protein-coupled receptor (GPCR) that plays a major role in the generation and modulation indicate that lateral diffusion parameters of serotonin1A receptors in normal cells are consistent with models

provides an extensive review on the current status of ligand development targeting LPA receptors to modulate

Our previous Markov State Model (MSM) analysis of molecular dynamics simulations of membrane-embedded

development of ligands targeting the binding site of endogenous ligands (orthosteric site), allosteric modulators Recent advances in the structure determination of GPCRs bound to different types of allosteric modulators structures available today, will facilitate structure-based discovery and development of allosteric modulators location of allosteric pockets, receptor-ligand interactions, and the chemical features of the allosteric modulators

work at SIRS2022 confirming the ability of the highly selective novel GPR52 agonist HTL00411718 to modulate

Previous pharmacophore modeling studies of the β3 -AR did not involve experimental in vitro validation Ligand-based pharmacophore modeling was performed since no 3D structure of human β3 -AR is yet available A dataset consisting of β3 -AR agonists was prepared to build and validate the pharmacophore models. The best model was employed for prospective virtual screening, followed by physicochemical property filtering

October 2022 ADGRL3 genomic variation implicated in neurogenesis and ADHD links functional effects to the incretin polypeptide GIP "Attention deficit/hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder. Single nucleotide polymorphisms (SNPs) in the Adhesion G Protein-Coupled Receptor L3 (ADGRL3) gene are associated with increased susceptibility to developing ADHD worldwide. However, the effect of ADGRL3 non-synonymous SNPs (nsSNPs) on the ADGRL3 protein function is vastly unknown. Using several bioinformatics tools to evaluate the impact of mutations, we found that nsSNPs rs35106420, rs61747658, and rs734644, previously reported to be associated and in linkage with ADHD in disparate populations from the world over, are predicted as pathogenic variants. Docking analysis of rs35106420, harbored in the ADGLR3-hormone receptor domain (HRM, a common extracellular domain of the secretin-like GPCRs family), showed that HRM interacts with the Glucose-dependent insulinotropic polypeptide (GIP), part of the incretin hormones family. GIP has been linked to the pathogenesis of diabetes mellitus, and our analyses suggest a potential link to ADHD. Overall, the comprehensive application of bioinformatics tools showed that functional mutations in the ADGLR3 gene disrupt the standard and wild ADGRL3 structure, most likely affecting its metabolic regulation. Further in vitro experiments are granted to evaluate these in silico predictions of the ADGRL3-GIP interaction and dissect the complexity underlying the development of ADHD." Read more at the source #DrGPCR #GPCR #IndustryNews

August 2022 Addex and Indivior Extend GABAB Positive Allosteric Modulator Research Collaboration for Therapeutics (SIX and Nasdaq: ADXN), a clinical-stage pharmaceutical company pioneering allosteric modulation-based discovering and developing novel oral gamma-aminobutyric acid subtype B (GABAB) positive allosteric modulator

revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate by negative or positive allosteric modulators. promising target for the treatment of psychiatric and neurodegenerative diseases, and several allosteric modulators The four compounds with the highest affinities were demonstrated to be negative allosteric modulators