Projects
In our projects, we combine our strong expertise in X-ray crystallography, cryo-EM and NMR spectroscopy with biochemistry, biophysics, and cell biology.
- Structural basis of bacterial transcription repression
- Structure-based drug discovery
Structural basis of bacterial transcription repression
Bacterial repressors play a crucial role in gene transcription regulation. The GntR and SorC/DeoR families are major groups of metabolic gene regulators. Despite their significance, the molecular mechanisms underlying their regulatory functions remain largely unknown. Understanding their three-dimensional structure is essential for unraveling these processes and can have implications for other family members. We focused on members of the SorC/DeoR family in B. subtilis: bsDeoR and bsCggR, representing distinct subfamilies. Through crystal structure determination, we uncovered the DNA recognition mechanism of these regulators by examining their N-terminal DNA binding domains in complex with minimal operator sequences. Moreover, we structurally characterized the full-length proteins bound to complete DNA operators. Our findings revealed a shared global architecture and a common DNA binding mechanism between the two repressors. This study presents a fundamental mechanism for the function of SorC family transcriptional regulators, laying the groundwork for future basic and applied research in this field.
Structure-based drug discovery
In our drug discovery projects, we target enzymes involved in diseases using protein structure knowledge for designing inhibitors. We also employ fragment-based drug discovery to find small molecules that disrupt protein-protein interactions in hematological malignancies.
Our main focus is on human carbonic anhydrases (CA), which have significant roles in physiological and pathological processes, making them potential diagnostic and therapeutic targets. We specifically aim to develop selective inhibitors for the tumor-specific CA IX isoform. Recently, we completed a project on carborane inhibitors for tumor-specific CA IX. These novel inhibitors combine a bulky inorganic cluster with an alkylsulfamide or alkylsulfonamide group, resulting in potent and selective inhibition. Preclinical studies demonstrated low toxicity, favorable pharmacokinetics, and the ability to reduce tumor growth. Cluster-containing inhibitors of CA IX show promise as candidates for drug development and/or combination therapy in boron neutron capture therapy.