Our main interest is in discovering how various classes of regulatory proteins within living cells act as allosteric molecular switches, together forming biomolecular logic circuits that detect incoming signals and orchestrate cellular responses.
We mainly use structural biology methods, in particular X-ray crystallography, small-angle X-ray scattering (SAXS), cryo-EM and nuclear magnetic resonance (NMR). These techniques are complemented by a variety of classical molecular biology methods as well as biochemical and biophysical approaches.
Specific research projects are listed below. Recent publications can be found here.
Gene regulation by repressors, activators, cofactors and small-molecule effectors
We are analysing a variety of prokaryotic (e.g. the TetR/AcrR family) and eukaryotic (e.g. PC4, nuclear receptors) transcription (co)factors, with the aim of understanding the allosteric mechanisms that enable these proteins to act as high-fidelity molecular switches.
Polyphosphate-dependent regulation of antibiotic production in microorganisms
Recent work in collaboration with the group of M.-J. Virolle at the Université Paris-Saclay (France) has revealed that polyphosphate-interacting proteins have a major impact on antibiotic production in bacteria of the genus Streptomyces. We are trying to unravel the mechanisms behind this biomedically important phenomenon and shed light on the biological significance of polyphosphate, a ubiquitous but poorly characterised molecule that is often described as the “neglected biopolymer”.
Viral replication
We are interested in various aspects of viral replication mechanisms, bacteriophage T5 DNA replication in particular. We have identified several highly unusual proteins that form a part of the T5 DNA replication machinery (this includes the bacteriophage’s long-elusive single-standed DNA binding protein), and we are unravelling the exact processes that these factors facilitate. We are also involved in several Covid19 drug design projects (text in German), aimed at inhibiting both viral proteases.
Signal transduction cascades comprising Ras-like GTPases
We are studying the small GTPase Ras/p21 and its cofactors, in particular the giant GAP (GTPase-activating protein) and tumour suppressor NF1, a 600 kDa homodimer whose structure we have recently elucidated to 3.7 Å using cryo-EM.
Developing novel expression and purification techniques that enable production of highly unstable proteins
Protein production remains a major hurdle in molecular and structural biology alike, in particular where regulatory proteins with a high degree of structural flexibility are concerned. We are developing ground-breaking strategies to deal with the inherent instability and toxicity of such targets.