A5059348833- Estrogen and related hormone effects
- HER2/EGFR in Cancer Research
- Cancer Immunotherapy and Biomarkers
- Melanoma and MAPK Pathways
- Microbial metabolism and enzyme function
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Colorectal Cancer Treatments and Studies
- Porphyrin Metabolism and Disorders
- Enzyme function and inhibition
- Photosynthetic Processes and Mechanisms
- Metal-Catalyzed Oxygenation Mechanisms
- Cytokine Signaling Pathways and Interactions
- Monoclonal and Polyclonal Antibodies Research
- Cancer therapeutics and mechanisms
- Enzyme Production and Characterization
- Microbial Metabolites in Food Biotechnology
- Enzyme Catalysis and Immobilization
- Protein Structure and Dynamics
- Immune cells in cancer
- Radiopharmaceutical Chemistry and Applications
- Asthma and respiratory diseases
- Protein Kinase Regulation and GTPase Signaling
- Chemical Reactions and Isotopes
- Inflammatory mediators and NSAID effects
MSD (Netherlands)
2012-2020
Kyushu University
2015
Merck (Netherlands)
2011-2015
University of East Anglia
2002-2006
University of Calgary
2005
University of Groningen
1999-2002
European Molecular Biology Laboratory
2000-2002
Abstract RORγt is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report discovery a novel allosteric binding site on nuclear receptor RORγt. Co-crystallization ligand domain (LBD) series small-molecule antagonists demonstrates occupancy previously unreported pocket. Binding at this non-canonical induces an unprecedented conformational reorientation helix 12 in LBD, which blocks cofactor binding. The functional...
Abstract Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell–specific regulators simultaneously modulate tumor immunity and another oncogenic pathway then used it identify 38 candidate immune–metabolic regulators. We show activities of these stratify patients with melanoma by their response anti–PD-1 using machine learning deep neural approaches, which...
Neoadjuvant chemoradiotherapy (nCRT) improves outcomes in resectable esophageal adenocarcinoma (EAC), but acquired resistance precludes long-term efficacy. Here, we delineate these mechanisms. RNA sequencing on matched patient samples obtained pre-and post-neoadjuvant treatment reveal that oxidative phosphorylation was the most upregulated of all biological programs following nCRT. Analysis patient-derived models confirms mitochondrial content and oxygen consumption strongly increase...
The twin-arginine transport (Tat) system is a protein-targeting pathway of prokaryotes and chloroplasts. Most Escherichia coli Tat substrates are complex metalloenzymes that must be correctly folded assembled before transport, preexport chaperone-mediated "proofreading" process therefore in operation. paradigm proofreading chaperone TorD, which coordinates maturation export the key respiratory enzyme trimethylamine N-oxide reductase (TorA). It demonstrated here purified TorD binds tightly...
Quinoprotein alcohol dehydrogenases are redox enzymes that participate in distinctive catabolic pathways enable bacteria to grow on various alcohols as the sole source of carbon and energy. The x-ray structure quinohemoprotein dehydrogenase from Comamonas testosteroni has been determined at 1.44 Å resolution. It comprises two domains. N-terminal domain a β-propeller fold binds one pyrroloquinoline quinone cofactor calcium ion active site. A tetrahydrofuran-2-carboxylic acid molecule is...
The progesterone receptor is able to bind a large number and variety of ligands that elicit broad range transcriptional responses ranging from full agonism antagonism numerous mixed profiles inbetween. We describe here two new ligand binding domain x-ray structures bound compounds structurally related but functionally divergent series, which show different modes corresponding their agonistic or antagonistic nature. In addition, we present third dimer an agonist in monomer A antagonist B,...
Soluble glucose dehydrogenase (s-GDH) from the bacterium Acinetobacter calcoaceticus is a classical quinoprotein. It requires cofactor pyrroloquinoline quinone (PQQ) to catalyze oxidation of gluconolactone. The precise catalytic role PQQ in s-GDH and several other PQQ-dependent enzymes has remained controversial because absence comprehensive structural data. We have determined crystal structure ternary complex with methylhydrazine, competitive inhibitor enzyme. This complex, refined at 1.5-Å...
Post-translational maturation of cytochromes c involves the covalent attachment heme to Cys-Xxx-Xxx-Cys-His motif apo-cytochrome. For this process, two cysteines must be in reduced state. In bacteria, is achieved by dedicated, membrane-bound thiol-disulfide oxidoreductases with a high reducing power, which are essential components cytochrome systems and also linked cellular disulfide-bond formation machineries. Here we report high-resolution structures oxidized states soluble, functional...
The p38α mitogen-activated protein kinase regulates the synthesis of pro-inflammatory cytokines in response to stimulation by a diverse set stress signals. Various different chemotypes and clinical candidates that inhibit function have been reported over years. In this publication, novel structure cocrystallized with candidate TAK-715 is reported. Owing impact crystallization conditions on conformation kinases (and particular p38α), structures complexes SB-203580, SCIO-469 VX-745 also...
A water-soluble aldose sugar dehydrogenase (Asd) has been purified for the first time from Escherichia coli. The enzyme is able to act upon a broad range of sugars, encompassing hexoses, pentoses, disaccharides, and trisaccharides, oxidize glucose gluconolactone with subsequent hydrolysis gluconic acid. shows ability bind pyrroloquinoline quinone (PQQ) in presence Ca2+ manner that proportional its catalytic activity. x-ray structure determined apo-form as PQQ-bound active holoenzyme....
The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment autoimmune diseases. nuclear hormone receptor RORγt is a master regulator cells affects production host cytokines, including IL-17A, IL-17F, IL-22, IL-26, GM-CSF. Substantial interest been spurred across both academia industry to seek small molecules suitable inhibition. A variety inhibitors have reported in past few years, majority which are orthosteric...
ResA, an extracytoplasmic thioredoxin from <i>Bacillus subtilis</i>, acts in cytochrome <i>c</i> maturation by reducing the disulfide bond present apocytochromes prior to covalent attachment of heme. This reaction is (and has be) specific, as broad substrate specificity would result unproductive shortcircuiting with general oxidizing thioredoxin(s) same compartment. Using mutational analysis and subsequent biochemical structural characterization active site variants, we show that reduced...
Over the past years, improvements in high-throughput screening (HTS) technology and compound libraries have resulted a dramatic increase amounts of good-quality hits, there is growing need for follow-on hit profiling assays with medium throughput to further triage hits. Here authors present such colony-stimulating factor 1 receptor (CSF1R, Fms), including tests cellular activity homogeneous assay measure affinity inactive CSF1R. They also target residence time, which based on competitive...
Membrane-intrinsic nitric oxide reductases (NORs) are key components of bacterial denitrification pathways with a close evolutionary relationship to the cytochrome oxidase (COX) complex found in aerobic respiratory chains. A distinction between COX and NOR is identity metal directly opposite heme b3 within active site. In NOR, this iron (FeB), whereas COX, it copper (CuB). The purified Roseobacter denitrificans contains has modest activity, raising possibility that COX-like site might have...
Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) cytoreductive surgery in resectable patients shows limited benefit, novel treatments urgently needed. The majority CRC-PMs represent CMS4 molecular subtype CRC, here we queried vulnerabilities this pharmacogenomic databases identify therapies. This reveals copper ionophore elesclomol...
Factor XI (FXI) is a key enzyme in the coagulation pathway and an attractive target for development of anticoagulant drugs. A small number high-resolution crystal structures FXIa complex with synthetic inhibitors have been published to date. All these ligands basic P1 group bind exclusively nonprime side active site FXIa. Here, two nonbasic that occupy both prime sides are presented. These new could be valuable design optimization synthethic inhibitors.