A5018188079- Computational Drug Discovery Methods
- RNA modifications and cancer
- SARS-CoV-2 and COVID-19 Research
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Neurogenetic and Muscular Disorders Research
- Peptidase Inhibition and Analysis
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- Microbial Metabolic Engineering and Bioproduction
- Advanced Electron Microscopy Techniques and Applications
- Iron Metabolism and Disorders
- Synthesis and biological activity
- COVID-19 Clinical Research Studies
- Metabolomics and Mass Spectrometry Studies
- interferon and immune responses
- Trace Elements in Health
- Protein Structure and Dynamics
- Peroxisome Proliferator-Activated Receptors
- Glycosylation and Glycoproteins Research
- Diverse Scientific Research Studies
- Autophagy in Disease and Therapy
- Infectious Encephalopathies and Encephalitis
- Protein Degradation and Inhibitors
Max Planck Institute for Biophysical Chemistry
2013-2025
Max Planck Institute for Multidisciplinary Sciences
2022-2024
Max Planck Institute for Dynamics and Self-Organization
2022-2024
Max Planck Society
2007-2020
University of Würzburg
2005-2014
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug available to directly treat the disease. In a search for against COVID-19, we have performed high-throughput x-ray crystallographic screen of two repurposing libraries main protease (M
Insights into proteasome inhibition Proteasomes are large protein complexes that degrade and remove proteins to maintain proper cellular physiology growth. a validated target for anticancer therapy, but drug design has been hampered by poor understanding of how inhibitors interact with the active site. Schrader et al. succeeded in crystallizing various proteasome-inhibitor complexes. They subsequently obtained crystal structures native human eight different inhibitor at resolutions between...
The activated spliceosome (B act ) is in a catalytically inactive state and remodeled into active machine by the RNA helicase Prp2, but mechanism unclear. Here, we describe 3D electron cryomicroscopy structure of Saccharomyces cerevisiae B complex at 5.8-angstrom resolution. Our model reveals that , catalytic U2/U6 RNA-Prp8 ribonucleoprotein core already established, 5′ splice site (ss) oriented for step 1 catalysis occluded protein. first-step nucleophile—the branchsite adenosine—is...
Abstract Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The main protease (M pro ), a cysteine with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M subject to redox regulation vitro and reversibly switches between enzymatically active dimer functionally dormant monomer through modifications residues. These include disulfide-dithiol switch catalytic C145...
Inevitably, viruses depend on host factors for their multiplication. Here, we show that hepatitis C virus (HCV) RNA translation and replication depends Rck/p54, LSm1, PatL1, which regulate the fate of cellular mRNAs from to degradation in 5'-3'-deadenylation-dependent mRNA decay pathway. The requirement these proteins efficient HCV was linked 5' 3' untranslated regions (UTRs) viral genome. Furthermore, LSm1-7 complexes specifically interacted with essential cis-acting elements located UTRs....
The ability to utilize a hybrid-photon-counting detector its full potential can significantly influence data quality, collection speed, as well development of elaborate acquisition schemes. This paper facilitates the optimal use EIGER2 detectors by providing theory and practical advice on (i) relation between design, technical specifications operating modes, (ii) corrections calibrations, (iii) new features: double-gating mode, 8-bit readout mode for increasing temporal resolution, lines...
Abstract If and how proteasomes catalyze not only peptide hydrolysis but also splicing is an open question that has divided the scientific community. The debate so far been based on immunopeptidomics, in vitro digestions of synthetic polypeptides as well ex vivo experiments, which could indirectly describe proteasome-catalyzed full-length proteins. Here we develop a workflow—and cognate software - to analyze proteasome-generated non-spliced spliced peptides produced from entire proteins...
Proteasomes catalyze protein degradation in cells and play an integral role cellular homeostasis. Its activity decreases with age alongside the load of defective proteins, resulting from mutations or oxidative stress-induced damage. Such proteins are prone to aggregation and, if not efficiently degraded, can form toxic oligomers amyloid plaques. Developing effective way activate proteasome could prevent such pathologies. Designing activators is easy because they do bind active site, which...
Assembly of the Sm-class U-rich small nuclear ribonucleoprotein particles (U snRNPs) is a process facilitated by macromolecular survival motor neuron (SMN) complex. This entity promotes binding set factors, termed LSm/Sm proteins, onto snRNA to form core structure these particles. Nine including SMN protein, product spinal muscular atrophy (SMA) disease gene, Gemins 2-8 and unrip have been identified as major components So far, however, only little known about architecture this complex...
Distal spinal muscular atrophy type 1 (DSMA1) is an autosomal recessive disease that clinically characterized by distal limb weakness and respiratory distress. In this disease, the degeneration of α-motoneurons caused mutations in immunoglobulin μ-binding protein 2 (IGHMBP2). This has been implicated DNA replication, pre-mRNA splicing transcription, but its precise function all these processes remained elusive. We have purified catalytically active recombinant IGHMBP2, which enabled us to...
In vertebrates, assembly of spliceosomal uridine-rich small nuclear ribonucleoproteins (UsnRNPs) is mediated by the SMN complex, a macromolecular entity composed proteins and Gemins 2-8. Here we have studied evolution this machinery using complete genome assemblies multiple model organisms. The complex has gained complexity in blockwise addition onto an ancestral core Gemin2. contrast to overall evolutionary trend more metazoans, orthologs most are missing dipterans. accordance with these...
The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity essential for cellular homeostasis. Thus, it an attractive target development of chemotherapeutics. While structural basis core particle (CP) inhibitors largely understood, their impact on remains entirely elusive. Here, we determined structure 26S with and without inhibitor Oprozomib. Drug binding modifies energy landscape conformational motion in regulatory (RP). Structurally, barrier created by...
Abstract Selection of the translation start codon is a key step during protein synthesis in human cells. We obtained cryo-EM structures 48S initiation complexes and characterized intermediates recognition by kinetic methods using eIF1A as reporter. Both approaches capture two distinct ribosome populations formed on an mRNA with cognate AUG presence eIF1, eIF1A, eIF2–GTP–Met-tRNAiMet eIF3. The ‘open’ 40S subunit conformation differs from scanning complex represents intermediate preceding...