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Advances in X-ray diffraction contrast tomography University of Antwerp
Diffraction contrast tomography is a near-field diffraction-based imaging technique that provides high-resolution grain maps of polycrystalline materials simultaneously with the orientation and average elastic strain tensor components of the individual grains with an accuracy of a few times 10(-4). Recent improvements that have been introduced into the data analysis are described. The ability to process data from arbitrary detector positions ...
Small-angle X-ray scattering and light scattering study of hybrid nanoparticles composed of thermoresponsive triblock copolymer F127 and thermoresponsive statistical polyoxazolines with hydrophobic moieties University of Antwerp
A combination of new thermoresponsive statistical polyoxazolines, poly[(2-butyl-2-oxazoline)-stat-(2-isopropyl-2-oxazoline)] [pBuOx-co-piPrOx], with different hydrophobic moieties and F127 surfactant as a template system for the creation of thermosensitive nanoparticles for radionuclide delivery has recently been tested [Pánek, Filippov, Hrubý, Rabyk, Bogomolova, Kučka & Stěpánek (2012). Macromol. Rapid Commun.33, 16831689]. It was shown ...
Structural comparison of protiated, H/D-exchanged and deuterated human carbonic anhydrase IX Vrije Universiteit Brussel
Human carbonic anhydrase IX (CA IX) expression is upregulated in hypoxic solid tumours, promoting cell survival and metastasis. This observation has made CA IX a target for the development of CA isoform-selective inhibitors. To enable structural studies of CA IX-inhibitor complexes using X-ray and neutron crystallography, a CA IX surface variant (CA IXSV; the catalytic domain with six surface amino-acid substitutions) has been developed that ...
A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1 Hasselt University
The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPyTM ("SAR by X-ray Poses Quickly") platform, which is applicable to any X-ray ...
Structural and biophysical characterization of Staphylococcus aureus SaMazF shows conservation of functional dynamics. Vrije Universiteit Brussel
The Staphylococcus aureus genome contains three toxin-antitoxin modules, including one mazEF module, SamazEF. Using an on-column separation protocol we are able to obtain large amounts of wild-type SaMazF toxin. The protein is well-folded and highly resistant against thermal unfolding but aggregates at elevated temperatures. Crystallographic and nuclear magnetic resonance (NMR) solution studies show a well-defined dimer. Differences in structure ...
A nanobody modulates the p53 transcriptional program without perturbing its functional architecture Vrije Universiteit Brussel Ghent University
The p53 transcription factor plays an important role in genome integrity. To perform this task, p53 regulates the transcription of genes promoting various cellular outcomes including cell cycle arrest, apoptosis or senescence. The precise regulation of this activity remains elusive as numerous mechanisms, e.g. posttranslational modifications of p53 and (non-)covalent p53 binding partners, influence the p53 transcriptional program. We developed a ...
Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response Hasselt University
Cancer will directly affect the lives of over one-third of the population. The DNA Damage Response (DDR) is an intricate system involving damage recognition, cell cycle regulation, DNA repair, and ultimately cell fate determination, playing a central role in cancer etiology and therapy. Two primary therapeutic approaches involving DDR targeting include: combinatorial treatments employing anticancer genotoxic agents; and synthetic lethality, ...
The Intrinsically Disordered Domain of the Antitoxin Phd Chaperones the Toxin Doc Against Irreversible Inactivation and Misfolding Vrije Universiteit Brussel University of Antwerp
The toxin Doc from the phd/doc toxin-antitoxin module targets the cellular translation machinery and is inhibited by its antitoxin partner Phd. Here we show that Phd also functions as a chaperone, keeping Doc in an active, correctly folded conformation. In absence of Phd, Doc exists in a relatively expanded state that is prone to dimerization through domain swapping with its active site loop acting as hinge region. The domain-swapped dimer is ...
An intrinsically disordered entropic switch determines allostery in Phd-Doc regulation Vrije Universiteit Brussel
Conditional cooperativity is a common mechanism involved in transcriptional regulation of prokaryotic type II toxin-antitoxin operons and is intricately related to bacterial persistence. It allows the toxin component of a toxin-antitoxin module to act as a co-repressor at low doses of toxin as compared to antitoxin. When toxin level exceeds a certain threshold, however, the toxin becomes a de-repressor. Most antitoxins contain an intrinsically ...