such applications, however, is a clearer understanding of how these drugs exert their effects at the molecular Here we review the current knowledge regarding the molecular details of psychedelic drug actions and

August 2022 "Psychedelic research across different disciplines and biological levels is growing at a

Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces

Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement

high-resolution structures of CB1 receptor in different functional states have significantly improved our molecular

Targeting rhodopsin with small molecule chaperones to improve the folding and stability of the mutant This review provides an update on the current knowledge regarding small molecule compounds that have

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics Non-equilibrium molecular simulation approaches are proven to be useful in this purpose. Here, we have implemented an optimized approach of combining the data derived from steered molecular

Though most of these variants exhibit a loss of function, the molecular defects caused by these underlying However, the magnitude of the response to this molecule varies considerably across this spectrum of mutations

To elucidate the molecular mechanisms responsible for these effects of RNA editing, we present four active-state

A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor (GPCR) for 19F-NMR and single-molecule

December 2021 Perkins’ Head of Molecular Endocrinology and Pharmacology, Professor Kevin Pfleger, was

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

September 2022 "G protein‐coupled receptors (GPCRs) are valuable therapeutic targets for many diseases. A central question of GPCR drug discovery is to understand what determines the agonism or antagonism of ligands that bind them. 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 that mediate their action and that among a large dataset of different ligands, the functionally important interactions will be over‐represented. 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. We used machine learning (ML) techniques to identify specific interactions that correlate with the agonist or antagonist activity of these ligands. We demonstrate with the application of ML methods that it is possible to identify the key interactions associated with agonism or antagonism of ligands. The most representative interactions for agonist ligands involve K972.68×67, F194ECL2, S2035.42×43, S2045.43×44, S2075.46×641, H2966.58×58, and K3057.32×31. Meanwhile, the antagonist ligands made interactions with W2866.48×48 and Y3167.43×42, both residues considered to be important in GPCR activation. The interpretation of ML analysis in human understandable form allowed us to construct an exquisitely detailed structure‐activity relationship that identifies small changes to the ligands that invert their pharmacological activity and thus helps to guide the drug discovery process. This approach can be readily applied to any drug target." Read more at the source #DrGPCR #GPCR #IndustryNews

of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular

Recent structural studies shed light on the molecular mechanisms involved in GPCR-arrestin coupling,

two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways on the molecular By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway

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

Molecular dynamics simulations support the local conformational flexibilities and different stabilities

Moreover, molecular docking was applied to valid the important interactions between the ingredients and enrichment analysis indicated that the mechanism of KXS in treating depression was involved in the biological Moreover, molecular docking results showed that Polygalaxanthone III, Girinimbine and Pachymic acid performed

August 2022 "Single particle cryogenic-electron microscopy (cryo-EM) is used extensively to determine structures of activated G protein-coupled receptors (GPCRs) in complex with G proteins or arrestins. However, applying it to GPCRs without signaling proteins remains challenging because most receptors lack structural features in their soluble domains to facilitate image alignment. In GPCR crystallography, inserting a fusion protein between transmembrane helices 5 and 6 is a highly successful strategy for crystallization. Although a similar strategy has the potential to broadly facilitate cryo-EM structure determination of GPCRs alone without signaling protein, the critical determinants that make this approach successful are not yet clear. Here, we address this shortcoming by exploring different fusion protein designs, which lead to structures of antagonist bound A2A adenosine receptor at 3.4 Å resolution and unliganded Smoothened at 3.7 Å resolution. The fusion strategies explored here are likely applicable to cryo-EM interrogation of other GPCRs and small integral membrane proteins." Read more at the source #DrGPCR #GPCR #IndustryNews

Therefore, it is imperative to understand the precise molecular mechanism of H2R biology.

Electron cryo-microscopy (cryo-EM) is a powerful technique for the structural characterization of biological Structural characterization of biologics, such as vaccines, viral vectors, and gene therapy agents, has

mechanism of the Delta opioid receptor by an agonist ADL5859 started from inactive conformation using molecular In this study, a DOR agonist ADL5859 was docked to the inactive DOR and multiple microsecond molecular R146, R258 and others) involving in the activation pathway were identified through the conventional molecular

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

The computational modeling and the 1.5-μs molecular dynamics data presented in the current study are C5a-C5aR2 interaction compared to C5a-C5aR1, which will surely help in elaborating the currently debated biological

biology. intersection of genomics and GPCR research sparked a new era of a comprehensive understanding of GPCR biology The integration of genomics with structural biology, pharmacology, bioinformatics, and clinical research has opened new avenues for exploring GPCR biology, developing targeted therapies, and translating genomic Current opinion in structural biology, 55, 161–177. https://doi.org/10.1016/j.sbi.2019.04.007 Papasergi-Scott

August 2022 "Oxysterols induce the migration of B-lymphocytes and dendritic cells to interfollicular regions of lymphoid tissues through binding the EBI2 (GPR183) to stimulate effective adaptive immunity and antibody production during infection. Aberrant EBI2 signaling is implicated in inflammatory bowel disease, sclerosis, and infectious disease. Here, we report the cryo-EM structures of an EBI2-Gi signaling complex with its endogenous agonist 7α,25-OHC and that of an inactive EBI2 bound to the inverse agonist GSK682753A. These structures reveal an agonist binding site for the oxysterol and a potential ligand entrance site exposed to the lipid bilayer. Mutations within the oxysterol binding site and the Gαi interface attenuate G protein signaling and abolish oxysterol-mediated cell migration indicating that G protein signaling directly involves in the oxysterol-EBI2 pathway. Together, these findings provide new insight into how EBI2 is activated by an oxysterol ligand and will facilitate the development of therapeutic approaches that target EBI2-linked diseases." Read more at the source #DrGPCR #GPCR #IndustryNews

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