The main interest of our laboratory is to understand molecular principles of signal transduction events under physiological conditions and in human disease. We investigate them at the level of enzymatic function and molecular structure of signaling proteins. Our current focus is on understanding how membrane-associated kinases, such as receptor tyrosine kinases, assemble into functional complexes and interface with the plasma membrane. We also investigate alternative non-catalytic roles of kinase scaffolds and seek to identify small molecule inhibitors that target these poorly understood kinase functions in human diseases.
Main Areas of Interest:
Structure-function studies of receptor tyrosine kinase activation mechanism: We use structural biology approaches, including X-ray crystallography and electron microscopy (cryo-EM), to gain high resolution insights into ligand-dependent activation of the receptor tyrosine kinase complexes, propagation of conformational changes in the receptor domains across the plasma membrane, and interaction of the receptors with their downstream effectors. To validate our structural models, we use quantitative cell-based functional assays, such as phospo-flow cytometry.
Understanding how cell membrane participates in cellular signaling by multi-protein signaling assemblies: By using various technologies of the in vitro membrane reconstitution, we use synthetic approaches to build signaling units comprising receptor tyrosine kinases and their interacting partners in vitro. This allows us to study how the stoichiometry and kinetic properties of receptor activation are regulated by the membrane environment. In collaboration with the Verba lab, we are developing approaches for visualization of these complexes at high resolution by cryo-EM.
Understudied protein kinases: Most of research focuses on few protein kinases leaving large portion of human kinome unexplored. Around 10% of all kinases in the human genome do not even have catalytic activity, but are essential for cellular homeostasis and frequently misregulated in human diseases. We are interested in elucidating the structural and functional basis for the understudied and atypical kinase functions, and ultimately in their modulation by small molecules with the goal of developing effective therapeutics.