A5037213868- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- Trypanosoma species research and implications
- Macrophage Migration Inhibitory Factor
- Genetics and Neurodevelopmental Disorders
- Plant Virus Research Studies
- Cancer-related gene regulation
- Chemical Reactions and Isotopes
- Peptidase Inhibition and Analysis
- DNA and Nucleic Acid Chemistry
- Education and Character Development
- Carbon dioxide utilization in catalysis
- Immunotherapy and Immune Responses
- Signaling Pathways in Disease
- Insect symbiosis and bacterial influences
- Click Chemistry and Applications
- Nuclear Receptors and Signaling
- Crystallography and molecular interactions
- Medical Imaging and Pathology Studies
- Crystallization and Solubility Studies
- Ubiquitin and proteasome pathways
- X-ray Diffraction in Crystallography
Wellcome Centre for Cell Biology
2021-2024
University of Edinburgh
2021-2024
University of Groningen
2015-2023
University of Copenhagen
2017
Leiden University
2013
Abstract The correct establishment of DNA methylation patterns is vital for mammalian development and achieved by the de novo methyltransferases DNMT3A DNMT3B. DNMT3B localises to H3K36me3 at actively transcribing gene bodies via its PWWP domain. It also functions heterochromatin through an unknown recruitment mechanism. Here, we find that knockout causes loss predominantly H3K9me3-marked domain mutations or deletion result in striking increases heterochromatin. Removal N-terminal region...
Preclinical models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a critical role the chemokine receptor 2 (CCR2) ligand (CCL2). However, one biggest problems high-affinity inhibitors CCR2 is their lack efficacy in clinical trials. We report new approach for design long-residence-time antagonists. developed competition association assay CCR2, which allows us investigate relation structure its residence time [i.e.,...
The postsynaptic density protein of 95 kDa (PSD-95) is a key scaffolding that controls signaling at synapses in the brain through interactions its PDZ domains with C-termini receptors, ion channels, and enzymes. PSD-95 highly regulated by phosphorylation. To explore effect phosphorylation on PSD-95, we used semisynthetic strategies to introduce phosphorylated amino acids four positions within examined effects large set binding partners. We observed complex affinity. Most notably, Y397...
KAT8 is a lysine acetyltransferase primarily catalyzing the acetylation of Lys16 histone H4 (H4K16). dysregulation linked to development and metastatization many cancer types, including non-small cell lung (NSCLC) acute myeloid leukemia (AML). Few inhibitors have been reported so far, none which displaying selective activity. Based on KAT3B/KDAC inhibitor C646, we developed series N-phenyl-5-pyrazolone derivatives identified compounds 19 34 as low-micromolar over panel KATs KDACs. Western...
Lysine acetyltransferase 8 (KAT8) is a histone (HAT) responsible for acetylating lysine 16 on H4 (H4K16) and plays role in cell cycle progression as well acetylation of the tumor suppressor protein p53. Further studies its biological function drug discovery initiatives will benefit from development small molecule inhibitors this enzyme. As first step towards aim we investigated enzyme kinetics bi-substrate The kinetic experiments indicate ping-pong mechanism which binds Ac-CoA first,...
Abstract Eukaryotes have a multitude of diverse mechanisms for organising and using their genomes, but the histones that make up chromatin are highly conserved. Unusually, from kinetoplastids divergent. The structural functional consequences this variation unknown. Here, we biochemically structurally characterised nucleosome core particles (NCPs) kinetoplastid parasite Trypanosoma brucei. A structure T. brucei NCP reveals global histone architecture is conserved, specific sequence...
Abstract Eukaryotes have a multitude of diverse mechanisms for organising and using their genomes, but the histones that make up chromatin are highly conserved. Unusually, from kinetoplastids divergent. The structural functional consequences this variation unknown. Here, we biochemically structurally characterised nucleosome core particles (NCPs) kinetoplastid parasite Trypanosoma brucei . A structure T. NCP reveals global histone architecture is conserved, specific sequence alterations lead...
Abstract DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining methylation patterns. However, the mechanisms underlying DNMT3A recruitment to function within different chromatin environments remain unclear. Using combination of biochemical structural approaches we find that interacts using multiple interfaces with chromatin; directly binding generic nucleosome features as well site-specific post-translational histone modifications. The N-terminal region,...
Abstract The correct establishment of DNA methylation patterns is vital for mammalian development and achieved largely by the de novo methyltransferases DNMT3A DNMT3B. Mutations in DNMT3B can cause immunodeficiency-centromeric instability-facial anomalies type 1 (ICF1) syndrome which characterised hypomethylated heterochromatin. However, genome, primarily localises to actively transcribing gene bodies through interaction its PWWP domain with histone modification H3K36me3 it unclear how...