A5009946736- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Helicobacter pylori-related gastroenterology studies
- Cancer Treatment and Pharmacology
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Viral Infectious Diseases and Gene Expression in Insects
- Cell death mechanisms and regulation
- bioluminescence and chemiluminescence research
- Metal-Catalyzed Oxygenation Mechanisms
- Veterinary medicine and infectious diseases
- Hemoglobin structure and function
- Cancer-related Molecular Pathways
- Bacteriophages and microbial interactions
- Neuropeptides and Animal Physiology
- Protein Kinase Regulation and GTPase Signaling
- Galectins and Cancer Biology
- Ubiquitin and proteasome pathways
- Click Chemistry and Applications
- interferon and immune responses
- S100 Proteins and Annexins
- Inflammasome and immune disorders
University of Zurich
2016-2025
Novartis (Switzerland)
1996-2001
Max Planck Institute for Medical Research
1996
University of Freiburg
1992-1994
University of Cambridge
1993
Abstract TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis frontotemporal dementia. Here, we report that physiological mouse human brain forms homo-oligomers are resistant to cellular stress. Physiological oligomerization mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed 2.1 Å crystal structure combination...
The cysteine protease CPP32 has been expressed in a soluble form Escherichia coli and purified to >95% purity. three-dimensional structure of human complex with the irreversible tetrapeptide inhibitor acetyl-Asp-Val-Ala-Asp fluoromethyl ketone was determined by x-ray crystallography at resolution 2.3 Å. asymmetric unit contains (p17/p12)2 tetramer, agreement tetrameric protein solution as dynamic light scattering size exclusion chromatography. overall topology is very similar that...
Primordial sequence signatures in modern proteins imply ancestral origins tracing back to simple peptides. Although short peptides seldom adopt unique folds, metal ions might have templated their assembly into higher-order structures early evolution and imparted useful chemical reactivity. Recapitulating such a biogenetic scenario, we combined design laboratory transform zinc-binding peptide globular enzyme capable of accelerating ester cleavage with exacting enantiospecificity high...
Expanding the range of genetically encoded metal coordination environments accessible within tunable protein scaffolds presents excellent opportunities for creation metalloenzymes with augmented properties and novel activities. Here, we demonstrate that installation a noncanonical Nδ-methyl histidine (NMH) as proximal heme ligand in oxygen binding myoglobin (Mb) leads to substantial increases redox potential promiscuous peroxidase activity. Structural characterization this catalytically...
Anthocyanins are ubiquitous plant pigments used in a variety of technological applications. Yet, after over century research, the penultimate biosynthetic step to anthocyanidins attributed action leucoanthocyanidin dioxygenase has never been efficiently reconstituted outside plants, preventing construction heterologous cell factories. Through biochemical and structural analysis, here we show that anthocyanin-related glutathione transferases, currently implicated only anthocyanin transport,...
Abstract Transforming growth factors β belong to a group of cytokines that control cellular proliferation and differentiation. Five isoforms are known share approximately 75% sequence identity, but exert different biological activities. The structure TGF‐β3 was solved by X‐ray crystallography refined final R ‐factor 17.5% at 2.0 Å resolution. Comparison with the TGF‐β2 (Schlunegger MP, Grütter MG, 1992, Nature 358 :430‐434; Daopin S, Piez KA, Ogawa Y, Davies DR, Science 257 :369‐373) reveals...
Abstract Inhibitors of the interaction between p53 tumor‐suppressor protein and its natural human inhibitor HDM2 are attractive as potential anticancer agents. In earlier work we explored designing β‐hairpin peptidomimetics α‐helical epitope on that would bind tightly to p53‐binding site HDM2. The is used a scaffold display energetically hot residues in an optimal array for with initial lead mimetic, weak inhibitory activity (IC 50 =125 μ M ), was optimized afford cyclo‐( L...
We have selected designed ankyrin repeat proteins (DARPins) from a synthetic library by using ribosome display that selectively bind to the mitogen-activated protein kinase ERK2 (extracellular signal-regulated 2) in either its nonphosphorylated (inactive) or doubly phosphorylated (active) form. They do not other kinases tested. Crystal structures of complexes with two DARPins, each specific for one forms, were obtained. The DARPins essentially same region kinase, but recognize conformational...
The discovery of the key role Toll-like receptors (TLRs) in initiating innate immune responses and modulating adaptive immunity has revolutionized our understanding vertebrate defence against pathogens. Yet, despite their central pathogen recognition initiation, there is little information on how variation TLRs influences disease susceptibility natural populations. Here, we assessed extent naturally occurring polymorphisms at TLR2 wild bank voles (Myodes glareolus) tested for associations...
Abstract Many tripartite motif-containing (TRIM) proteins, comprising RING-finger, B-Box and coiled-coil domains, carry additional B30.2 domains on the C-terminus of TRIM motif are considered to be pattern recognition receptors involved in detection higher order oligomers (e.g. viral capsid proteins). To investigate spatial architecture proteins we determined crystal structure TRIM20Δ413 fragment at 2.4 Å resolution. This comprises central helical scaffold (CHS) C-terminal reveals an...
Enzymes rely on complex interactions between precisely positioned active site residues as a mechanism to compensate for the limited functionality contained within genetic code. Heme enzymes provide striking example of this complexity, whereby electronic properties reactive ferryl intermediates are finely tuned through hydrogen bonding proximal ligands and neighboring amino acids. Here, we show that introduction chemically programmed Nδ-methyl histidine (NMH) ligand into an engineered...
Adenoviruses (Ads) have shown promise as vectors for gene delivery in clinical trials. Efficient viral targeting to a tissue of choice requires both ablation the virus’ original tropism and engineering an efficient receptor-mediated uptake by specific cell population. We developed series adapters binding virus with such high affinity that they remain fully bound >10 d, block its natural receptor site mediate interaction surface choice. The adapter contains two fused modules, consisting...
Stimulation of regulatory T (Treg) cells holds great promise for the treatment autoimmune, chronic inflammatory, and certain metabolic diseases. Recent clinical trials with low-dose interleukin-2 (IL-2) to expand Treg led beneficial results in autoimmunity, but IL-2 immunotherapy can activate both pathogenic cells. Use receptor α (IL-2Rα, CD25)-biased IL-2/anti-IL-2 antibody complexes improves selectivity cells; however, mechanism action such is incompletely understood, thus hampering their...
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...
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....
Temperature influences the reaction kinetics and evolvability of all enzymes. To understand how evolution shapes thermodynamic drivers catalysis, we optimized modest activity a computationally designed enzyme for an elementary proton-transfer by nearly 4 orders magnitude over 9 rounds mutagenesis screening. As theorized primordial enzymes, catalytic effects original design were almost entirely enthalpic in origin, as rate enhancements achieved laboratory evolution. However, large reductions...
Abstract Changing the primary metal coordination sphere is a powerful strategy for tuning metalloprotein properties. Here we used amber stop codon suppression with engineered pyrrolysyl‐tRNA synthetases, including two newly evolved enzymes, to replace proximal histidine in myoglobin N δ ‐methylhistidine, 5‐thiazoylalanine, 4‐thiazoylalanine and 3‐(3‐thienyl)alanine. In addition heme redox potential over >200 mV range, these noncanonical ligands modulate protein's carbene transfer activity...
Nitrene transfer reactions catalyzed by heme proteins have broad potential for the stereoselective formation of carbon-nitrogen bonds. However, competition between productive nitrene and undesirable reduction precursors limits implementation such biocatalytic methods. Here, we investigated azides model protein myoglobin to gain mechanistic insights into factors that control fate key reaction intermediates. In this system, proceeds via a proposed intermediate is rapidly reduced protonated...
We determined the first structure of PRYSPRY, a domain found in over 500 different proteins, involved innate immune signaling, cytokine signaling suppression, development, cell growth and retroviral restriction. The fold encompasses 7‐stranded 6‐stranded antiparallel β‐sheet, arranged β‐sandwich. In crystal, PRYSPRY forms dimer where C‐terminus an acceptor molecule binds to concave surface donor molecule, which represents putative interaction site. Mutations domains Pyrin, are responsible...
Abstract The crystal structure of the dimeric flavoenzyme glutathione reductase from Escherichia coli was determined and refined to an R ‐factor 16.8% at 1.86 Å resolution. molecular 2‐fold axis dimer is local but very close a possible crystallographic axis; slight asymmetry could be rationalized packing contacts. 2 crystallographically independent subunits are virtually identical, yielding no structural clue on cooperativity. compared with well‐known homologous enzyme human erythrocytes 52%...