Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode.

ABSTRACT: Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using S-adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.

SUBMITTER: Pande V

PROVIDER: S-EPMC7667828 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action.

Project description:ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

| S-EPMC6218015 | biostudies-literature

Erythrocyte glutathione transferase: a general probe for chemical contaminations in mammals.

Project description:Glutathione transferases (GSTs) are enzymes devoted to the protection of cells against many different toxins. In erythrocytes, the isoenzyme (e-GST) mainly present is GSTP1-1, which is overexpressed in humans in case of increased blood toxicity, as it occurs in nephrophatic patients or in healthy subjects living in polluted areas. The present study explores the possibility that e-GST may be used as an innovative and highly sensitive biomarker of blood toxicity also for other mammals. All distinct e-GSTs from humans, Bos taurus (cow), Sus scrofa (pig), Capra hircus (goat), Equus caballus (horse), Equus asinus (donkey) and Ovis aries (sheep), show very similar amino acid sequences, identical kinetics and stability properties. Reference values for e-GST in all these mammals reared in controlled farms span from 3.5±0.2 U/gHb in the pig to 17.0±0.9 U/gHb in goat; such activity levels can easily be determined with high precision using only a few microliters of whole blood and a simple spectrophotometric assay. Possibly disturbing factors have been examined to avoid artifact determinations. This study provides the basis for future screening studies to verify if animals have been exposed to toxicologic insults. Preliminary data on cows reared in polluted areas show increased expression of e-GST, which parallels the results found for humans.

| S-EPMC4979413 | biostudies-literature

PRMT5 methyl proteomics in MiaPaca2 cells

Project description:Goal: To determine total PRMT5 methyl substrates and those that function through the novel substrate adaptor binding site

2022-06-13 | PXD019991 | Pride

Discovery of a novel fluorescent chemical probe suitable for evaluation of neuropilin-1 binding of small molecules.

Project description:Neuropilin-1 (NRP1) is emerging as an important molecule in immune signaling where it has been shown to modulate the actions of TGF-β1 in macrophages and regulatory T cells. The development of cost-effective and reliable assays for NRP1 binding is therefore important. We synthesized three new NRP1 small molecule fluorophores and examined their performance as fluorescent polarization probes. One molecule DS108 exhibited favorable binding and fluorescent characteristics and allowed us to establish a simple assay suitable for medium to high throughput screening of small molecules.

| S-EPMC7317715 | biostudies-literature

Neural stem cell specific fluorescent chemical probe binding to FABP7.

Project description:Fluorescent small molecules have become indispensable tools for biomedical research along with the rapidly developing optical imaging technology. We report here a neural stem cell specific boron-dipyrromethane (BODIPY) derivative compound of designation red 3 (CDr3), developed through a high throughput/content screening of in-house generated diversity oriented fluorescence library in stem cells at different developmental stages. This novel compound specifically detects living neural stem cells of both human and mouse origin. Furthermore, we identified its binding target by proteomic analysis as fatty acid binding protein 7 (FABP7), also known as brain lipid binding protein) which is highly expressed in neural stem cells and localized in the cytoplasm. CDr3 will be a valuable chemical tool in the study and applications of neural stem cells.

| S-EPMC3387064 | biostudies-literature

Dishevelled3 is a novel arginine methyl transferase substrate.

Project description:Dishevelled, a phosphoprotein scaffold, is a central component in all the Wnt-sensitive signaling pathways. In the present study, we report that Dishevelled is post-translationally modified, both in vitro and in vivo, via arginine methylation. We also show protein arginine methyl transferases 1 and 7 as the key enzymes catalyzing Dishevelled methylation. Interestingly, Wnt3a stimulation of F9 teratocarcinoma cells results in reduced Dishevelled methylation. Similarly, the methylation-deficient mutant of Dishevelled, R271K, displayed spontaneous membrane localization and robust activation of Wnt signaling; suggesting that differential methylation of Dishevelled plays an important role in Wnt signaling. Thus arginine methylation is shown to be an important switch in regulation of Dishevelled function and Wnt signaling.

| S-EPMC3496165 | biostudies-other

Dual DNA binding mode of a turn-on red fluorescent probe thiazole coumarin.

Project description:Turn-on fluorescent probes show enhanced emission upon DNA binding, advocating their importance in imaging cellular DNA. We have probed the DNA binding mode of thiazole-coumarin (TC) conjugate, a recently reported hemicyanine-based turn-on red fluorescent probe, using a number of biophysical techniques and a series of short oligonucleotides. TC exhibited increased fluorescence anisotropy and decreased absorbance (~50%) at low [DNA]/[TC] ratio. Although the observed hypochromicity and the saturating value of [DNA base pair]:[TC] ratio is consistent with a previous study that suggested intercalation to be the DNA binding mode of TC, a distinctly different and previously unreported binding mode was observed at higher ratios of [DNA]:[TC]. With further addition of DNA, only oligonucleotides containing AnTn or (AT)n stretches showed further change-decreased hypochromicity, red shifted absorption peaks and concomitant fluorescence enhancement, saturating at about 1:1 [DNA]: [TC]. 1H-NMR chemical shift perturbation patterns and H1'-H6/H8 NOE cross-peaks of the 1:1 complex indicated minor groove binding by TC. ITC showed the 1:1 DNA binding event to be endothermic (ΔH° ~ 2 kcal/mol) and entropy driven (ΔS° ~ 32 cal/mol/K). Taken together, the experimental data suggest a dual DNA binding mode by TC. At low [DNA]/[TC] ratio, the dominant mode is intercalation. This switches to minor groove binding at higher [DNA]/[TC], only for sequences containing AnTn or (AT)n stretches. Turn-on fluorescence results only in the previously unreported minor groove bound state. Our results allow a better understanding of DNA-ligand interaction for the newly reported turn-on probe TC.

| S-EPMC7497988 | biostudies-literature

GSK8814: a chemical probe fort he ATAD2 bromodomain

Project description:Differential gene expression analysis of LNCaP cells treated with GSK8814 and GSK8815 Total RNA obtained from cells treated with GSK8814 and GSK8815 for 24 hours

2016-09-01 | E-GEOD-78868 | biostudies-arrayexpress

When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

Project description:Traditional hit-to-lead optimization assumes that upon elaboration of chemical structure, the ligand retains its binding mode relative to the receptor. Here, we build a large-scale collection of related ligand pairs solved in complex with the same protein partner: we find that for 41 of 297 pairs (14%), the binding mode changes upon elaboration of the smaller ligand. While certain ligand physiochemical properties predispose changes in binding mode, particularly those properties that define fragments, simple structure-based modeling proves far more effective for identifying substitutions that alter the binding mode. Some ligand pairs change binding mode because the added substituent would irreconcilably conflict with the receptor in the original pose, whereas others change because the added substituent enables new, stronger interactions that are available only in a different pose. Scaffolds that can engage their target using alternate poses may enable productive structure-based optimization along multiple divergent pathways.

| S-EPMC5525026 | biostudies-literature