A5064418161- Advanced NMR Techniques and Applications
- Electron Spin Resonance Studies
- Protein Structure and Dynamics
- Quantum and electron transport phenomena
- Histone Deacetylase Inhibitors Research
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- Enzyme Structure and Function
- Genetic Neurodegenerative Diseases
- Chemical Synthesis and Analysis
- Neurogenetic and Muscular Disorders Research
- Cardiovascular Function and Risk Factors
- NF-κB Signaling Pathways
- Hemoglobin structure and function
- Protein Degradation and Inhibitors
- Protein Kinase Regulation and GTPase Signaling
- Spectroscopy and Quantum Chemical Studies
- ATP Synthase and ATPases Research
- RNA regulation and disease
- Advanced Fluorescence Microscopy Techniques
- interferon and immune responses
- Melanoma and MAPK Pathways
- Protein Tyrosine Phosphatases
- Receptor Mechanisms and Signaling
- Circadian rhythm and melatonin
University of Copenhagen
2016-2024
University College London
2011-2020
Institute of Structural and Molecular Biology
2011-2020
University College Copenhagen
2020
Brown University
2017
Hospital Madre Teresa
2015
Birkbeck, University of London
2011
The transcriptional corepressor complex CoREST is one of seven histone deacetylase complexes that regulate the genome through controlling chromatin acetylation. unique in containing both demethylase and enzymes, LSD1 HDAC1, held together by RCOR1 scaffold protein. To date, it has been assumed enzymes function independently within complex. Now, we report assembly ternary Using structural functional studies, show activity two closely coupled can exist at least distinct states with different...
Abstract Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds certain human proteins is the cause polyQ disorders. To study structural basis association between tract length, disease, we addressed how conformation androgen receptor, associated spinobulbar muscular atrophy (SBMA), depends on its length. Here report that this folds into...
Owing to their plasticity, intrinsically disordered and multidomain proteins require descriptions based on multiple conformations, thus calling for techniques analysis tools that are capable of dealing with conformational ensembles rather than a single protein structure. Here, we introduce DEER-PREdict, software program predict Double Electron-Electron Resonance distance distributions as well Paramagnetic Relaxation Enhancement rates from conformations. DEER-PREdict uses an established...
Abstract Förster resonance energy transfer (FRET) is a widely-used and versatile technique for the structural characterization of biomolecules. Here, we introduce FRETpredict, an easy-to-use Python software to predict FRET efficiencies from ensembles protein conformations. FRETpredict uses rotamer library approach describe probes covalently bound protein. The efficiently flexibly operates on large conformational such as those generated by molecular dynamics simulations facilitate validation...
Mitogen-activated protein kinases, which include p38, are essential for cell differentiation and autophagy. The current model p38 activation involves activation-loop phosphorylation with subsequent substrate binding leading to phosphorylation. Despite extensive efforts, the molecular mechanism of remains unclear. Here, using NMR spectroscopy, we show how modulation dynamics across timescales activates p38. We find that does not change average conformation p38; rather it quenches loop ps-ns...
Iron-catalyzed generation of free radicals leads to molecular damage in vivo, and has been proposed contribute organismal ageing. Here we investigate the role iron ageing nematode Caenorhabditis elegans. Media supplementation with Fe(III) increased levels as detected by continuous-wave electron paramagnetic resonance spectroscopy elevated expression iron-sensitive reporter transgene pftn-1::gfp. Increased caused protein oxidation hypersensitivity tert-butyl hydroperoxide (t-BOOH) given 9 mM...
Phosphorylation is one of the main regulators cellular signaling typically occurring in flexible parts folded proteins and intrinsically disordered regions. It can have distinct effects on chemical environment as well structural properties near modification site. Secondary shift analysis NMR method for detection transiently formed secondary structure (IDPs) reliability depends an appropriate choice random coil model. Random shifts sequence correction factors were previously determined...
Abstract Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these themselves. Here, we show HDAC8 allosterically regulated by shifts populations between exchanging states. An inactive state identified, which stabilised a range mutations resembles sparsely-populated equilibrium with active HDAC8. Computational models states...
The human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and has been identified as drug target for the treatment of several cancers. Previously HDAC8 enzyme extensively studied using biochemical techniques, X-ray crystallography, computational methods. Those investigations have yielded detailed information about active site demonstrated that substrate entrance surface highly dynamic. Yet it remained unclear how dynamics tune influence catalytic activity HDAC8. Using...
The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising a desired conformation. In recent years, the copper-catalysed azide-alkyne cycloaddition (CuAAC) has emerged as powerful method stapling. However, to date CuAAC stapling not provided simple obtaining that are easily diversified further. present study, we report new diversity-oriented (DOPS) methodology based on chemistry....
Abstract Here, we introduce FRETpredict, a Python software program to predict FRET efficiencies from ensembles of protein conformations. FRETpredict uses an established Rotamer Library Approach describe the probes covalently bound protein. The efficiently operates on large conformational such as those generated by molecular dynamics simulations facilitate validation or refinement models and interpretation experimental data. We demonstrate performance accuracy for different types systems:...
We present pulsed electron-nuclear double resonance (ENDOR) experiments which enable us to characterize the coupling between bismuth donor spin qubits in Si and surrounding bath of 29Si impurities provides dominant decoherence mechanism (nuclear diffusion) at low temperatures (< 16 K). Decoupling from is predicted cluster correlation expansion simulations show near-complete suppression diffusion, optimal working points. The takes form sharply peaked divergences diffusion coherence time,...
A natural bond orbital (NBO) analysis of unpaired electron spin density in metalloproteins is presented, which allows a fast and robust calculation paramagnetic NMR parameters. Approximately 90% the occupies metal–ligand NBOs, allowing majority to be modeled by only few NBOs that reflect chemical bonding environment. We show relaxation rate protons can calculated accurately using these rates are good agreement with corresponding measured experimentally. This holds, particular, for ligand...
Abstract The adaptor protein Grb2 is a key element of mitogenetically important signaling pathways. With its SH2 domain it binds to upstream targets while SH3 domains bind downstream proteins thereby relaying signals from the cell membranes nucleus. by recognizing phosphotyrosine (pY) in pYxNx peptide motif, requiring an Asn at +2 position C‐terminal pY with residue either side this being hydrophobic. Structural analysis complex cognate has shown that adopts unique β‐turn conformation,...
A series of Gs protein peptidomimetics were designed and synthesised based on the published X-ray crystal structure active state β2-adrenergic receptor (β2AR) in complex with (PDB 3SN6). We hypothesised that such may function as allosteric modulators target intracellular binding site β2AR. Peptidomimetics to mimic 15 residue C-terminal α-helix pre-organised a helical conformation by (i, i + 4)-stapling using copper catalysed azide alkyne cycloaddition. Linear stapled analysed circular...
Abstract Owing to their plasticity, intrinsically disordered and multidomain proteins require descriptions based on multiple conformations, thus calling for techniques analysis tools that are capable of dealing with conformational ensembles rather than a single protein structure. Here, we introduce DEER-PREdict, software predict Double Electron-Electron Resonance distance distributions as well Paramagnetic Relaxation Enhancement rates from conformations. DEER-PREdict uses an established...
VOLUME 290 (2015) PAGES 16539–16549 PAGE 16547: The panel showing IKKγ and GAPDH expression levels from 1.3E2 cells reconstituted with D242R was omitted Fig. 9C. NF-κB activation data for the mutant 9D. complete figure is shown. Download .zip (8.73 MB) Help zip files