A5010939853- Receptor Mechanisms and Signaling
- Chemokine receptors and signaling
- Chemical Thermodynamics and Molecular Structure
- Cancer-related gene regulation
- Neuropeptides and Animal Physiology
- Crystallography and molecular interactions
- Monoclonal and Polyclonal Antibodies Research
- RNA modifications and cancer
- Molecular Spectroscopy and Structure
- Cytokine Signaling Pathways and Interactions
- Mass Spectrometry Techniques and Applications
- Cancer, Hypoxia, and Metabolism
- Biochemical effects in animals
- HVDC Systems and Fault Protection
- RNA and protein synthesis mechanisms
- Folate and B Vitamins Research
- T-cell and B-cell Immunology
- Hypothalamic control of reproductive hormones
- Lanthanide and Transition Metal Complexes
- Chemical Reactions and Isotopes
- Fluorine in Organic Chemistry
- Immune Response and Inflammation
- Molecular spectroscopy and chirality
- Biochemical and Molecular Research
- Lipid Membrane Structure and Behavior
University of Copenhagen
2020-2024
University of Zurich
2019-2022
Abstract The RNA methylase METTL3 catalyzes the transfer of a methyl group from cofactor S‐adenosyl‐L‐methionine (SAM) to N 6 atom adenine. We have screened library 4000 analogues and derivatives adenosine moiety SAM by high‐throughput docking into METTL3. Two series adenine were identified in silico , binding mode six predicted inhibitors was validated protein crystallography. compounds, one for each series, show good ligand efficiency. propose route their further development potent selective
Both CXC chemokine receptor 4 (CXCR4) and atypical 3 (ACKR3) are activated by the CXCL12 yet evoke distinct cellular responses. CXCR4 is a canonical G protein–coupled (GPCR), whereas ACKR3 intrinsically biased for arrestin. The molecular basis this difference not understood. Here, we describe cryo-EM structures of in complex with CXCL12, more potent variant, small-molecule agonist. bound chemokines adopt an unexpected pose relative to those established observed other receptor-chemokine...
Chemokine receptors belong to the large class of G protein-coupled (GPCRs) and are involved in a number (patho)physiological processes. Previous studies highlighted importance membrane lipids for modulating GPCR structure function. However, underlying mechanisms how regulate GPCRs often poorly understood. Here, we report that anionic lipid bilayers increase binding affinity chemokine CXCL12 atypical receptor 3 (ACKR3) by kinetics. Notably, bilayer favors over more positively charged CXCL11,...
Neurotensin receptor 1 (NTSR1) and related G protein-coupled receptors of the ghrelin family are clinically unexploited, several mechanistic aspects their activation inactivation have remained unclear. Enabled by a new crystallization design, we present five structures: apo-state NTSR1 as well complexes with nonpeptide inverse agonists SR48692 SR142948A, partial agonist RTI-3a, novel full SRI-9829, providing structural rationales on how ligands modulate NTSR1. The favor large extracellular...
We have developed a homogeneous time-resolved fluorescence (HTRF)-based enzyme assay to measure the catalytic activity of N6-methyladenosine (m6A) methyltransferases and demethylases. The detects m6A modifications using natural m6A-binding proteins (m6A readers). reaction product or substrate m6A-containing RNA reader protein are fluorescently labeled such that their proximity during binding initiates Förster resonance energy transfer (FRET). show our HTRF can be used for high-throughput...
Abstract α-adrenergic receptors (αARs) are G protein-coupled that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential αARs, however, is largely unexploited hampered by scarcity subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to αARs or fail interact with desired subtype. Here, we report crystal structure human α 1B AR bound inverse agonist (+)-cyclazosin, enabled fusion a DARPin crystallization chaperone....
Chemokine receptors are extensively involved in a broad range of physiological and pathological processes, making them attractive drug targets. However, despite considerable efforts, there very few approved drugs targeting this class seven transmembrane domain to date. In recent years, the importance including binding kinetics discovery campaigns was emphasized. Therefore, kinetic insight into chemokine–chemokine receptor interactions could help address issue. Moreover, it additionally...
Atypical chemokine receptor 3 (ACKR3) is a seven transmembrane (TM) spanning heptahelical that involved in different stages of cancer progression. Unlike canonical G protein-coupled receptors (GPCRs), ACKR3 does not couple to heterotrimeric proteins when activated by its endogenous ligand, CXCL12. It therefore naturally occurring fully arrestin biased receptor. however desensitizes normally and contributes progression through arrestin-mediated signaling pathways and/or active sequestration...