A5015908566- RNA modifications and cancer
- DNA Repair Mechanisms
- Epigenetics and DNA Methylation
- Mass Spectrometry Techniques and Applications
- Receptor Mechanisms and Signaling
- Advanced Proteomics Techniques and Applications
- Nicotinic Acetylcholine Receptors Study
- Ubiquitin and proteasome pathways
- Neuroscience and Neuropharmacology Research
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Drug Transport and Resistance Mechanisms
- Cellular transport and secretion
- Protein Degradation and Inhibitors
- Molecular Sensors and Ion Detection
- Parkinson's Disease Mechanisms and Treatments
- Diet, Metabolism, and Disease
- Genomics and Phylogenetic Studies
- Biotin and Related Studies
- bioluminescence and chemiluminescence research
- Cytokine Signaling Pathways and Interactions
- Multiple Myeloma Research and Treatments
- Proteoglycans and glycosaminoglycans research
- S100 Proteins and Annexins
- Spinal Fractures and Fixation Techniques
Pfizer (United States)
2015-2025
Boston Medical Center
2024
BioWorks (United States)
2018
Ton Duc Thang University
2016-2017
Jülich Aachen Research Alliance
2012
German Research School for Simulation Sciences
2012
Max Planck Institute of Biochemistry
2011
Max Planck Society
2011
Scuola Internazionale Superiore di Studi Avanzati
2009-2010
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading ubiquitination subsequent degradation of the target. They present exciting opportunity modulate proteins in manner independent enzymatic or signaling activity. As such, they have recently emerged as attractive mechanism explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding parameters...
The turnover of each protein in the mammalian proteome is a functionally important characteristic. Here, we employed high-resolution mass spectrometry to quantify dynamics nondividing cells. ratio externally supplied versus endogenous amino acids de novo synthesis was about 17:1. Using subsaturating SILAC labeling, obtained accurate rates 4106 proteins HeLa and 3528 C2C12 Comparison these human mouse cell lines revealed highly significant correlation orthologs thus high species conservation....
PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level toward is achieved by covalent interaction a unique cysteine residue (Cys-909) in catalytic domain JAK3, which replaced serine Importantly, 10 kinases kinome have at equivalent position Cys-909 JAK3. Five those belong to TEC kinase family including BTK, BMX, ITK, RLK, and are also inhibited PF-06651600. Preclinical data demonstrate that inhibition cytolytic function...
Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver accumulation ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators the AMP-Activated Protein Kinase (AMPK) have been proposed as treatment for metabolic diseases; we show that AMPK β1-biased activator PF-06409577 capable lowering systemic levels both rodent monkey preclinical models. able inhibit de novo synthesis pathways, causes...
Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) have been linked to autosomal dominant Parkinson's disease. The most prevalent mutation, G2019S, results enhanced LRRK2 activity that potentially contributes the etiology of Consequently, disease progression is mediated by poorly characterized phosphorylation-dependent substrate pathways. To address this gap knowledge, we transduced SH-SY5Y neuroblastoma cells with G2019S via adenovirus, then determined quantitative changes...
Azurin from Pseudomonas aeruginosa is known anticancer bacteriocin, which can specifically penetrate human cancer cells and induce apoptosis. We hypothesized that pathogenic commensal bacteria with long term residence in body produce azurin-like bacteriocins as a weapon against the invasion of cancers. In our previous work, putative have been screened complete genomes 66 dominant species gut microbiota subsequently characterized by subjecting them functional annotation algorithms azurin...
DNA base lesions, such as incorporation of uracil into or mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair genomic uracil, we performed a CRISPR knockout screen the presence floxuridine, chemotherapeutic agent that incorporates fluoro-uracil DNA. We identified known factors, N-glycosylase (UNG), unknown N6-adenosine methyltransferase, METTL3, required overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence, product METTL3...
DNA base lesions, such as incorporation of uracil into or mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair genomic uracil, we performed a CRISPR knockout screen the presence floxuridine, chemotherapeutic agent that incorporates fluorouracil DNA. We identified known factors, N-glycosylase (UNG), unknown N6-adenosine methyltransferase, METTL3, required overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence, product METTL3...
Understanding how ligands bind to G-protein coupled receptors (GPCRs) provides insights into a myriad of cell processes and is crucial for drug development. Here we extend hybrid molecular mechanics/coarse-grained (MM/CG) approach applied previously enzymes GPCR/ligand complexes. The accuracy this method structural predictions established by comparison with recent atomistic dynamics simulations on the human β2 adrenergic receptor, member GPCRs superfamily. results obtained MM/CG methodology...
In the brain, high cognitive functions are encoded by coherent network oscillations. Key players inhibitory interneurons that, releasing GABA into principal cells, pace targeted cells. Among these, oriens-lacunosum moleculare (O-LM) that provide a theta frequency patterned output to distal dendrites of pyramidal cells endowed with HCN channels responsible for slowly activating inwardly rectifying I h current and their pacemaking activity. Here we show in transgenic mice expressing EGFP...
Targeted protein quantification using liquid chromatography–tandem mass spectrometry with stable isotope-labeled standards is recognized as the gold standard of practice for quantification. Such assays, however, can only cover a limited number proteins, and developing targeted methods larger numbers proteins requires substantial investment. Alternatively, large-scale global proteomic experiments along computational such "total approach" (TPA) have potential to provide extensive In this...
Recent evidence suggests that the extracellular protein milieu is much more complex than previously assumed as various secretome analyses from different cell types described release of hundreds to thousands proteins. The function many these proteins has yet be determined particularly in context three-dimensional tissues with abundant cell–cell contacts. Toward this goal, we developed a strategy dual SILAC labeling astrocytic cultures for silico exclusion unlabeled serum or neurons used...
Mitogen-activated protein kinase 4 (MAP4K4) regulates the MEK cascade and is implicated in cytoskeletal rearrangement migration; however, identifying MAP4K4 substrates has remained a challenge. To ascertain MAP4K4-dependent phosphorylation events, we combined phosphoproteomic studies of inhibition with vitro assessment its specificity. We identified 235 phosphosites affected by cells found that pTP pSP motifs were predominant among them. In contrast, specificity showed favors pTL motif....
Binding of small molecules to their targets triggers complex pathways. Computational approaches are keys for predictions the molecular events involved in such cascades. Here we review current efforts at characterizing determinants largest membrane-bound receptor family, G-protein-coupled receptors (GPCRs). We focus on odorant receptors, which constitute more than half GPCRs. The work presented this uncovers structural and energetic aspects components cellular cascade. Finally, a...
LSD1 is one of the important proteins which help transcriptional machine to access DNA though open or close around histone. It can also demethylate p53 at specific lysines altering p53-mediated process could lead inhibition role in promoting apoptosis. Thus, activity by small compounds becomes a promising cancer therapy. Combining Lipinski's rule with docking and steered molecular dynamics simulation we have found from traditional Chinese medicine database four that are good candidates for...
Download This Paper Open PDF in Browser Add to My Library Share: Permalink Using these links will ensure access this page indefinitely Copy URL DOI
Summary DNA base lesions, such as incorporation of uracil into or mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair genomic uracil, we performed a CRISPR knockout screen the presence floxuridine, chemotherapeutic agent that incorporates fluoro-uracil DNA. We identified known factors, N-glycosylase (UNG), but also unknown N6-adenosine methyltransferase, METTL3, required overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence,...
DNA base lesions, such as incorporation of uracil into or mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair genomic uracil, we performed a CRISPR knockout screen the presence floxuridine, chemotherapeutic agent that incorporates fluoro-uracil DNA. We identified known factors, N-glycosylase (UNG), unknown N6-adenosine methyltransferase, METTL3, required overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence, product METTL3...