A5085857181- Mass Spectrometry Techniques and Applications
- Advanced Proteomics Techniques and Applications
- Metabolomics and Mass Spectrometry Studies
- Protein Structure and Dynamics
- Analytical Chemistry and Chromatography
- Trace Elements in Health
- Alzheimer's disease research and treatments
- Protein Degradation and Inhibitors
- Ion-surface interactions and analysis
- Enzyme Structure and Function
- Parkinson's Disease Mechanisms and Treatments
- Histone Deacetylase Inhibitors Research
- Heat shock proteins research
- Chemical Synthesis and Analysis
- Iron Metabolism and Disorders
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Epigenetics and DNA Methylation
- Advanced Glycation End Products research
- Enzyme function and inhibition
- Ubiquitin and proteasome pathways
- Isotope Analysis in Ecology
- Nanoparticle-Based Drug Delivery
- Click Chemistry and Applications
Technical University of Darmstadt
2020-2025
University of Warwick
2017-2024
Coventry (United Kingdom)
2018-2021
University of Antwerp
2014-2019
Flemish Institute for Technological Research
2017
Province of Antwerp
2016-2017
Division of Chemistry
2016
In recent years, there has been increasing interest in top-down mass spectrometry (TDMS) approaches for protein analysis, driven both by technological advancements and efforts such as those the multinational Consortium Top-Down Proteomics (CTDP). Today, diverse sample preparation ionization methods are employed to facilitate TDMS analysis of denatured native proteins their complexes. The goals these studies vary, ranging from proteoform identification, determination binding site a...
Synchrotron soft X-ray nano-imaging and spectromicroscopy reveals iron calcium biomineralization in Alzheimer's disease amyloid plaques.
The chemistry of copper and iron plays a critical role in normal brain function. A variety enzymes proteins containing positively charged Cu
Molecular glues are a new drug modality with the potential to engage otherwise undruggable targets. However, rational discovery of molecular for desired targets is major challenge and most known have been discovered by serendipity. Here we present first fully synthetic FKBP12-mTOR glues, which were from FKBP-focused, target-unbiased ligand library. Our biochemical screening >1000 in-house FKBP ligands yielded one hit that induced dimerization FKBP12 FRB domain mTOR. The crystal structure...
Molecular glues (MGs) and proteolysis-targeting chimeras (PROTACs) are used to modulate protein–protein interactions (PPIs), via induced proximity between compounds that have little or no affinity for each other naturally. They promote either reversible inhibition selective degradation of a target protein, including ones deemed undruggable by traditional therapeutics. Though native MS (nMS) is capable analyzing multiprotein complexes, the behavior these artificially in gas phase still not...
Top-down approaches for the characterization of intact proteins and macromolecular complexes are becoming increasingly popular, since they potentially simplify speed up assignment process. Here we demonstrate how, on a commercially available Q-TWIMS-TOF instrument, performed top-down ETD native form tetrameric alcohol dehydrogenase. We achieved good sequence coverage throughout first 81 N-terminal amino acids ADH, with exception loop located inside protein. This is in agreement exposed parts...
Non-dissociative charge reduction, typically considered to be an unwanted side reaction in electron transfer dissociation (ETD) experiments, can enhanced significantly order reduce the state of intact protein complexes as low 1+ on a commercially available Q-IM-TOF instrument. This allows for detection large beyond 100,000 m/z, while at same time generating top-down ETD fragments, which provide sequence information from surface-exposed parts folded structure. Optimization supplemental...
Top-down sequencing approaches are becoming ever more popular for protein characterization, due to the ability distinguish and characterize different isoforms. Under non-denaturing conditions, electron transfer dissociation (ETD) can furthermore provide important information on exposed surface of proteins or complexes, thereby contributing characterization their higher-order structure. Here, we investigate this approach using top-down ETD tetrameric hemoglobin, concanavalin A, alcohol...
Electron-based fragmentation methods have revolutionized biomolecular mass spectrometry, in particular native and top-down protein analysis. Here, we report the use of a new electromagnetostatic cell to perform electron capture dissociation (ECD) within quadrupole/ion mobility/time-of-flight spectrometer. This was installed between ion mobility time-of-flight regions instrument, fast enough be compatible with separation. The instrument already fitted transfer (ETD) quadrupole prior...
Native top-down mass spectrometry is a fast, robust biophysical technique that can provide molecular-scale information on the interaction between proteins or peptides and ligands, including metal cations. Here we have analyzed complexes of full-length amyloid β (1-42) monomer with range (patho)physiologically relevant cations using native Fourier transform ion cyclotron resonance three different fragmentation methods-collision-induced dissociation, electron capture infrared multiphoton...
The FK506-binding protein 51 (FKBP51) is a promising target in variety of disorders including depression, chronic pain, and obesity. Previous FKBP51-targeting strategies were restricted to occupation the site, which does not affect core functions FKBP51. Here, we report discovery first FKBP51 proteolysis targeting chimera (PROTAC) that enables degradation abolishing its scaffolding function. Initial synthesis 220 FKBP-focused PROTACs yielded plethora active for FKBP12, six FKBP51, none...
Abstract Atypical low-oxidation-state iron phases in Alzheimer’s disease (AD) pathology are implicated pathogenesis, as they may promote elevated redox activity and convey toxicity. However, the origin of pathways responsible for its formation evolution remain unresolved. Here we investigate interaction AD peptide β-amyloid (Aβ) with storage protein ferritin, to establish whether interactions between these two species a potential source AD. Using X-ray spectromicroscopy electron microscopy...
Human histone deacetylase 4 (HDAC4) is a key epigenetic regulator involved in number of important cellular processes. This makes HDAC4 promising target for the treatment several cancers and neurodegenerative diseases, particular Huntington's disease. highly regulated by phosphorylation oxidation, which determine its nuclear or cytosolic localization, exerts function through multiple interactions with other proteins, forming multiprotein complexes varying composition. The catalytic domain...
Engineering at the amino acid level is key to enhancing properties of existing proteins in a desired manner. So far, protein engineering has been dominated by genetic approaches, which have extremely powerful but only allow for minimal variations beyond canonical acids. Chemical peptide synthesis allows unrestricted incorporation vast set unnatural acids with much broader functionalities, including post-translational modifications or labels. Here we demonstrate potential chemical generate...
The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks Alzheimer's disease. Altered metabolism essential biometals is another feature Alzheimer's, with representing sites disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding plaque composition the role metals associated them critical. To establish this knowledge, ability resolve chemical...
The DNA methyltransferase 2 (DNMT2) is an RNA modifying enzyme associated with pathophysiological processes, such as mental and metabolic disorders or cancer. Although the development of inhibitors remains challenging, DNMT2 not only a promising target for drug discovery, but also activity-based probes. Here, we present covalent SAH-based decorated new type aryl warhead. Based on noncovalent inhibitor N-benzyl substituent, Topliss scheme was followed optimization. results showed that...
Sulfonamides are one of the most important pharmacophores in medicinal chemistry, and sulfonamide analogues have gained substantial interest recent years. However, protein interactions sulfonamides especially their underexplored. Using FKBP12 as a model system, we describe synthesis optically pure sulfenamide, sulfinamide, sulfonimidamide well characterized ligand. This allowed us to precisely determine binding contributions each oxygen atom consequences nitrogen replacements. We also...
Oligonucleotide therapeutics have emerged as an important class of drugs offering targeted therapeutic strategies that complement traditional modalities, such monoclonal antibodies and small molecules. Their unique ability to precisely modulate gene expression makes them vital for addressing previously undruggable targets. A critical aspect developing these therapies is characterizing their molecular composition accurately. This includes determining the monoisotopic mass oligonucleotides,...
Owing to its versatility, electron transfer dissociation (ETD) has become one of the most commonly utilized fragmentation techniques in both native and non-native top-down mass spectrometry. However, several competing reactions-primarily different forms charge reduction-occur under ETD conditions, as evidenced by distorted isotope patterns usually observed. In this work, we analyze these compare stability nondissociative (ETnoD) products, specifically noncovalent c/z fragment complexes,...