A5017260514- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Adenosine and Purinergic Signaling
- Chemical Synthesis and Analysis
- HER2/EGFR in Cancer Research
- Chronic Myeloid Leukemia Treatments
- Glycosylation and Glycoproteins Research
- Microbial Natural Products and Biosynthesis
- Chronic Lymphocytic Leukemia Research
- Nuclear physics research studies
- Wnt/β-catenin signaling in development and cancer
- Neuropeptides and Animal Physiology
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Innovation and Knowledge Management
- Cancer-related gene regulation
- Protein Structure and Dynamics
- Fungal Plant Pathogen Control
- Quinazolinone synthesis and applications
- Nuclear Physics and Applications
- Mass Spectrometry Techniques and Applications
- Nicotinic Acetylcholine Receptors Study
- Biochemical and Structural Characterization
- Pharmacological Receptor Mechanisms and Effects
- Kruppel-like factors research
University of Bonn
1965-2024
Karolinska Institutet
2023-2024
Leipzig University
2023
Bocconi University
2014
Saarland University
2003-2007
Abstract The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize cultivable bacterial FR producer, enabling detailed investigations into biosynthesis attachment functionally important side chain. We reconstitute chain monomodular NRPS FrsA non-heme monooxygenase...
The Frizzled family of transmembrane receptors (FZD1–10) belongs to the class F G protein-coupled (GPCRs). FZDs bind and are activated by Wingless/Int1 (WNT) proteins. WNT/FZD signaling system regulates crucial aspects developmental biology stem-cell regulation. Dysregulation communication can lead defects diseases such as cancer fibrosis. Recent insight into activation mechanisms has underlined that protein dynamics conserved microswitches essential for FZD-mediated information flow build...
Frizzleds (ten paralogs: FZD
Heterotrimeric G protein subunits Gαq and Gα11 are inhibited by two cyclic depsipeptides, FR900359 (FR) YM-254890 (YM), both of which being used widely to implicate Gq/11 proteins in the regulation diverse biological processes. An emerging major research question therefore is whether cellular effects inhibitors on-target, that is, mediated via specific inhibition proteins, or off-target, result nonspecific interactions with other proteins. Here we introduce a versatile experimental strategy...
Guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. While GPCRs represent the largest class of drug targets, protein inhibition has only recently been recognized as a novel strategy for treating complex diseases such asthma, inflammation, and cancer. The structurally similar macrocyclic depsipeptides FR900359 (FR) YM-254890 (YM) are potent selective inhibitors Gq subfamily...
Abstract The G protein‐coupled adenosine A 2A receptor (A AR) is an important new (potential) drug target in immuno‐oncology, and for neurodegenerative diseases. Preladenant its derivatives belong to the most potent AR antagonists displaying exceptional selectivity. While crystal structures of human have been solved, mostly using ‐StaR2 protein that bears 9 point mutations, co‐crystallization with has so far elusive. We developed a construct harboring single mutation (S91 3.39 K) which...
Abstract The G s protein-coupled adenosine A 2A receptor (A AR) represents an emerging drug target for cancer immunotherapy. clinical candidate Etrumadenant was developed as AR antagonist with ancillary blockade of the 2B subtype. It constitutes a unique chemotype featuring poly-substituted 2-amino-4-phenyl-6-triazolylpyrimidine core structure. Herein, we report two crystal structures in complex Etrumadenant, obtained differently thermostabilized constructs. This led to discovery...
Wingless/Int-1 (WNT) signaling is mediated by WNT binding to 10 Frizzleds (FZD
The G protein-coupled receptor 17 (GPR17) is an orphan involved in inflammatory diseases. GPR17 antagonists have been proposed for the treatment of multiple sclerosis due to their potential induce remyelination. Potent, selective are required enable target validation. In present study, we describe discovery a novel class based on anthranilic acid scaffold. compounds' potencies were evaluated calcium mobilization and radioligand binding assays, structure–activity relationships analyzed....
Abstract The Wingless/Int-1 (WNT) signaling network is essential to orchestrate central physiological processes such as embryonic development and tissue homeostasis. In the currently held tenet, WNT/β-catenin initiated by WNT-induced recruitment of Frizzleds (FZDs) LRP5/6 followed formation a multiprotein signalosome complex. Here, we use bioluminescence resonance energy transfer (BRET) show that different WNT paralogs dynamically trigger FZD-LRP6 association. While receptor interaction was...
G proteins are intracellular switches that transduce and amplify extracellular signals from GPCRs. The Gq protein subtypes, which coupled to PLC activation, can act as oncogenes, their expression was reported be up-regulated in cancer inflammatory diseases. inhibition may an efficient therapeutic strategy constituting a new level of intervention. However, diagnostic tools drugs for lacking.We have now developed -specific, cell-permeable 3 H-labelled high-affinity probes based on the...
The adenosine A2B receptor (A2BAR) belongs to the rhodopsin-like G protein-coupled (GPCR) family. It is upregulated under hypoxic conditions, in inflammation and cancer. Previous studies indicated coupling of A2BAR different proteins, mainly Gs, but some cases Gq/11 or Gi, depending on cell type. We have now utilized novel technologies, (i) heterologous expression individual members Gαq/11 protein family (Gαq, Gα11, Gα14, Gα15) knockout cells, (ii) TRUPATH platform, allowing direct...
E-cadherin participates in homophilic cell-to-cell adhesion and is localized to intercellular junctions of the adherens type. In present study, we investigated localization junction components cells expressing mutant derivatives which had been previously cloned from diffuse-type gastric carcinoma. The mutations are frame deletions exons 8 or 9 a point mutation exon affect extracellular domain E-cadherin. Our findings indicate that mutated causes beta-catenin staining at lateral contact sites...
The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They important pharmacological tools have potential as therapeutic drugs. hydrogenated, tritium-labeled YM FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine dissociation kinetics unlabeled Gq protein inhibitors. Structure-affinity structure-residence time...
Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for immunotherapy cancer. In present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a,...