A5076218373- Advanced NMR Techniques and Applications
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Molecular spectroscopy and chirality
- RNA and protein synthesis mechanisms
- Chemical Synthesis and Analysis
- Prion Diseases and Protein Misfolding
- NMR spectroscopy and applications
- Metabolomics and Mass Spectrometry Studies
- Advanced MRI Techniques and Applications
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Analytical Chemistry and Chromatography
- Electron Spin Resonance Studies
- Viral Infectious Diseases and Gene Expression in Insects
- Computational Drug Discovery Methods
- Protein Kinase Regulation and GTPase Signaling
- Protein purification and stability
- Bacterial Genetics and Biotechnology
- Carbohydrate Chemistry and Synthesis
- Escherichia coli research studies
- thermodynamics and calorimetric analyses
- Supramolecular Self-Assembly in Materials
- Genomics and Chromatin Dynamics
- Solid-state spectroscopy and crystallography
ETH Zurich
2005-2025
University of Zurich
2024
Novartis (Switzerland)
2009-2020
Novartis Institutes for BioMedical Research
2010-2020
Institute of Molecular Biology and Biophysics
2020
École Polytechnique Fédérale de Lausanne
2018
University of Basel
2010
Natural microbial communities are phylogenetically and metabolically diverse. In addition to underexplored organismal groups1, this diversity encompasses a rich discovery potential for ecologically biotechnologically relevant enzymes biochemical compounds2,3. However, studying identify genomic pathways the synthesis of such compounds4 assigning them their respective hosts remains challenging. The biosynthetic microorganisms in open ocean largely uncharted owing limitations analysis...
The NMR structure of the recombinant elk prion protein (ePrP), which represents cellular isoform (ePrP C ) in healthy organism, is described here. As anticipated from highly conserved amino acid sequence, ePrP has same global fold as other mammalian proteins (PrPs), with a flexibly disordered “tail” residues 23–124 and globular domain 125–226 three α-helices short antiparallel β-sheet. However, shows striking local variation when compared most PrPs, particular human, bovine, mouse PrP . A...
Abstract Fluorine chemistry has taken a pivotal role in chemical reaction discovery, drug development, and biology. NMR spectroscopy, arguably the most important technique for characterization of fluorinated compounds, is rife with highly inconsistent referencing fluorine shifts, producing deviations larger than 1 ppm. Herein, we provide unprecedented evidence that both spectrometer design current unified scale system underpinning calibration heteronuclear spectra have unintentionally led to...
Fluorine NMR spectroscopy is widely used for detection of protein-ligand interactions in drug discovery because the simplicity fluorine spectra combined with a relatively high likelihood molecule to include at least one atom. In general, an important limitation its sensitivity, which results need unphysiologically protein concentrations and large ligand:protein ratios. An enhancement (19)F signal several thousand fold by dynamic nuclear polarization allows submicromolar fluorinated small...
The affinity between a chosen target protein and small molecules is key aspect of drug discovery. Screening by popular NMR methods such as Water-LOGSY suffers from low sensitivity false positives caused aggregated or denatured proteins. This work demonstrates that the can be greatly boosted injecting hyperpolarized water into solutions proteins ligands. Ligand binding detected in few seconds, whereas about 30 min usually required without hyperpolarization. Hyperpolarized also enhances proton...
Abstract The pandemic caused by SARS-CoV-2 has called for concerted efforts to generate new insights into the biology of betacoronaviruses inform drug screening and development. Here, we establish a workflow determine RNA recognition druggability nucleocapsid N-protein SARS-CoV-2, highly abundant protein crucial viral life cycle. We use synergistic method that combines NMR spectroscopy protein-RNA cross-linking coupled mass spectrometry quickly binding two domains N-protein. Finally, explore...
Molecular replacement in X-ray crystallography is the prime method for establishing structure-activity relationships of pharmaceutically relevant molecules. Such an approach not available NMR. Here, we establish a comparable method, called NMR molecular (NMR(2)). The requires experimentally measured ligand intramolecular NOEs and ligand-protein intermolecular as well previously known receptor structure or model. Our findings demonstrate that NMR(2) may open new avenue fast robust...
Abstract Hyperpolarization is generated by dissolution dynamic nuclear polarization (d‐DNP) using a polymer‐based polarizing agent dubbed FLAP (filterable labeled agents for polarization). It consists of thermo‐responsive poly( N ‐isopropylacrylamide), also known as p NiPAM‐COOH, with nitroxide radicals. The polymer powder impregnated an arbitrary solution interest and frozen is. Dissolution followed simple filtration, leading to hyperpolarized solutions free from any contaminants. We...
Abstract Current biological research increasingly focusses on large human proteins and their complexes. Such are difficult to study by NMR spectroscopy because they often can only be produced in higher eukaryotic expression systems, where deuteration is hardly feasible. Here, we present the XL‐ALSOFAST‐[ 13 C, 1 H]‐HMQC experiment with much improved sensitivity for fully protonated high molecular weight proteins. For tested systems ranging from 100 240 kDa size, 3‐fold was obtained average...
Abstract Fragment‐based lead discovery has become a fundamental approach to identify ligands that efficiently interact with disease‐relevant targets. Among the numerous screening techniques, fluorine‐detected NMR gained popularity owing its high sensitivity, robustness, and ease of use. To effectively explore chemical space, universal experiment, rationally designed fragment library, sample composition optimized for maximal number compounds minimal measurement time are required. Here, we...
Fucosylation patterns in cell‐surface glycans are essential mediators of recognition and signalling. Aberrations these signatures serve as vital diagnostic markers disease progression, so understanding fucose‐protein interactions at the molecular level is crucial. Molecular editing l‐fucose (Fuc) C2 with fluorine provides a platform to reconcile ubiquity fucosylation paucity strategies interrogate site‐specific interactions. Through judicious introduction pseudo‐equatorial [C(sp3)‐F]...
Fucosylation patterns in cell‐surface glycans are essential mediators of recognition and signalling. Aberrations these signatures serve as vital diagnostic markers disease progression, so understanding fucose‐protein interactions at the molecular level is crucial. Molecular editing l‐fucose (Fuc) C2 with fluorine provides a platform to reconcile ubiquity fucosylation paucity strategies interrogate site‐specific interactions. Through judicious introduction pseudo‐equatorial [C(sp3)‐F]...
For initial hit identification in fragment‐based drug design, NMR is one of the preferred methods, with well‐established ligand screening experiments T1ρ, waterLOGSY and STD. Here, we present a new, perfect echo‐based experiment superior binding sensitivity, PEARLScreen. The sensitivity enhancement based on longer relaxation delays as well active exchange broadening, enabled by echo scheme. This allowed reduction protein concentration up to order magnitude comparison conventional same setup...
For initial hit identification in fragment‐based drug design, NMR is one of the preferred methods, with well‐established ligand screening experiments T1ρ, waterLOGSY and STD. Here, we present a new, perfect echo‐based experiment superior binding sensitivity, PEARLScreen. The sensitivity enhancement based on longer relaxation delays as well active exchange broadening, enabled by echo scheme. This allowed reduction protein concentration up to order magnitude comparison conventional same setup...
Naturally competent bacteria can take up and incorporate free DNA from their environment using complex machinery that is endogenously encoded. This process called natural transformation a key mechanism in the spread of antibiotic resistance amongst bacteria, including many human pathogens. All require ComEC to transport transforming across cytoplasmic membrane. In addition transmembrane competence domain predicted form channel, most orthologues additionally contain an oligonucleotide binding...
The basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factor (TF) MYC is in large part an intrinsically disordered oncoprotein. In complex with its obligate heterodimerization partner MAX, preferentially binds E-Box DNA sequences (CANNTG). At promoters containing these sequence motifs, controls fundamental cellular processes such as cell cycle progression, metabolism, and apoptosis. A vast network of proteins turn regulates function via intermolecular interactions. this work, we...