A5015683098- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- Ubiquitin and proteasome pathways
- Calcium signaling and nucleotide metabolism
- Biochemical and Molecular Research
- RNA and protein synthesis mechanisms
- Immunodeficiency and Autoimmune Disorders
- Phytase and its Applications
- Endoplasmic Reticulum Stress and Disease
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Crystallization and Solubility Studies
- Pancreatic function and diabetes
- Autophagy in Disease and Therapy
- Carbohydrate Chemistry and Synthesis
- Click Chemistry and Applications
- RNA modifications and cancer
- X-ray Diffraction in Crystallography
- Genetic factors in colorectal cancer
- DNA Repair Mechanisms
- Protein Structure and Dynamics
- Metabolism, Diabetes, and Cancer
- RNA Research and Splicing
Leibniz-Forschungsinstitut für Molekulare Pharmakologie
2021-2024
Forschungsverbund Berlin
2023
University of Victoria
2016-2019
MRC Laboratory of Molecular Biology
2014-2017
Newly transcribed eukaryotic precursor messenger RNAs (pre-mRNAs) are processed at their 3' ends by the ~1-megadalton multiprotein cleavage and polyadenylation factor (CPF). CPF cleaves pre-mRNAs, adds a polyadenylate tail, triggers transcription termination, but it is unclear how its various enzymes coordinated assembled. Here, we show that nuclease, polymerase, phosphatase activities of yeast organized into three modules. Using electron cryomicroscopy, determined 3.5-angstrom-resolution...
Fanconi anaemia (FA) is a cancer predisposition syndrome characterized by cellular sensitivity to DNA interstrand crosslinkers. The molecular defect in FA an impaired repair pathway. critical event activating this pathway monoubiquitination of FANCD2. In vivo, multisubunit core complex catalyzes step, but its mechanism unclear. Here, we report purification native avian and biochemical reconstitution FANCD2 monoubiquitination. This demonstrates that the catalytic FANCL E3 ligase subunit must...
Significance Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in phosphoinositide 3-kinases (PI3Kδ). Activating either the p110δ catalytic or p85α regulatory subunit of PI3Kδ result APDS. Mutations leading to APDS are surprising, as other p85α-activating oncogenic when bound PI3Kα isoform. Using hydrogen–deuterium exchange mass spectrometry, we determined molecular mechanisms which activate and reveal why APDS2 mutant primarily...
Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated response to cellular nutrient status is poorly understood. We show here that lysosome morphology function reversibly controlled a nutrient-regulated lipid switch triggers conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active static mTORC1-inactive degradative lysosomes clustered at cell...
Type III phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking and implicated a variety of pathogenic processes. It key host factor replication RNA viruses. The design potent specific inhibitors this will be to define its cellular roles may lead novel antiviral therapeutics. We previously reported the PI4K inhibitor PIK93, compound has defined functions PI4KIIIβ. However, showed high cross reactivity with class I PI3Ks. Using structure-based drug...
Inositol poly- and pyrophosphates (InsPs PP-InsPs) are densely phosphorylated eukaryotic messengers, which involved in numerous cellular processes. To elucidate their signaling functions at the molecular level, non-hydrolyzable bisphosphonate analogs of inositol pyrophosphates, PCP-InsPs, have been instrumental. Here, an efficient synthetic strategy to obtain these unprecedented quantities is described - relying on use combined phosphate ester-phosphoramidite reagents. The PCP-analogs,...
Mildly reactive electrophiles have emerged as powerful functional groups for developing chemical probes to target pharmacologically important proteins and study key biological mechanisms. With the current manuscript, we introduce unsaturated N-alkyl-phosphonamidates a new class of warheads that enable proximity-induced labeling specific targeting protein-protein interactions. In contrast many other electrophilic warheads, these cysteine-selective can be incorporated into amino acid side on...
Abstract Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high...
Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency...
Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency...
Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency...
Uridine diphosphate N-acetylglucosamine 2-epimerase (GNE) is a key enzyme in the sialic acid biosynthesis pathway. Sialic acids are primarily terminal carbohydrates on glycans and play fundamental roles health disease. In search of effective GNE inhibitors not based carbohydrate scaffold, we performed high-throughput screening campaign 68,640 drug-like small molecules against recombinant using UDP detection assay. We validated nine primary actives with an orthogonal real-time NMR assay...
Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development potent IP6K inhibitors is gaining momentum, tool to distinguish mammalian isozymes still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed high-throughput screen identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency...