Pillars of our research
Biological motions, epigenetics and drugs
Medically important macromolecules under study include integral membrane proteins (IMPs) and large macromolecular assemblies, like epigenetic writers, and nucleosomes. The dynamics, structure and interactions of target proteins are probed for their mechanisms of their action and functioning. Further, we focus on translating my fundamental findings to biological processes and human disease and beyond towards potent therapeutics. For instance, the atomic resolution structures and dynamics of medically essential proteins in the absence and presence of various chemical compounds, like drugs, inhibitors and/or diagnostic as well as endogenous ligands (e.g., ATP, cholesterol, porphyrins, ions) reveal their functionality and uncover the underlying molecular bases of drugs action and cellular signaling mediated by the studied proteins. Among exciting systems where we strive to understand the molecular bases of their aberrant functioning in the human body leading to various cancers and seek small molecular therapeutics are human methyltransferases targeting lysine H3K36 (H3K36 KMTs) as H3K36 KMTs’ aberrations are identified in over 21% of all patients with diagnosed cancer.
Our primary tool of study is high-resolution nuclear magnetic resonance (NMR) spectroscopy. We constantly apply and develop NMR approaches with complementary biophysical methodologies to pursue NMR-based dynamics and structural studies towards challenging systems and interactions. This technique gives us access to both structure and functioning of medically important macromolecular systems and their mutual interactions at physiologically relevant conditions, like water solutions at physiological temperatures or lipid bilayers. In detail, we are interested in further developments of NMR spectroscopy techniques, particularly spin relaxation, giving access to a broader range of molecular motions and automation of the resonance assignment procedures that would facilitate both structural and dynamics studies of macromolecules. We also apply state-of-the-art complementary biophysical methods to study challenging macromolecular complexes, like X-ray crystallography, electron microscopy, molecular modelling, and molecular dynamics simulations.
We are further interested in NMR-based profiling of metabolites in human-derived biofluids from healthy and sick individuals, for which we perceive considerable potential in defining novel biomarkers. Here we use the existing NMR-based techniques and develop them to provide unprecedented resolution and accuracy in de novo detecting the metabolites from the complex biofluid mixtures, facilitating targeted and untargeted metabolism profiling. Our focus here is on increasing the number and confidence of identified metabolites from human samples by pushing both sample preparation and NMR methodologies forward. Furthermore, by combining data on metabolic changes associated with different stages of the disease with atomic-level information on gain-of-function tumour-driving mutations, one can expect to gain access to more powerful therapeutic and diagnostic solutions in cancer.