The Whitty Group studies protein-protein and protein-ligand recognition, with an emphasis on how binding energy from these intermolecular interactions can be utilized to achieve biological function or inhibition. We apply this research in two distinct areas: (i) developing a quantitative, mechanistic understanding of the activation and signaling of growth factor receptors, and (ii) advancing our ability to discover drugs that inhibit protein-protein interactions.
- Activation and signaling mechanisms in growth factor receptor systems. This work aims to address longstanding mechanistic questions concerning exactly how the binding of a cytokine or growth factor brings about an activated state of its receptor, and how the assembly of the activated receptor complex is quantitatively coupled to proximal and distal signaling events and to the ultimate cellular response (See Schlee et al., Nature Chemical Biology, 2006). The protein-protein interaction between NEMO and IKK, with the target site for inhibition highlighted by modeled fragment clusters (cyan and magenta stick representations)
- Discovery and characterization of small molecule (i.e. synthetic organic) inhibitors of protein-protein interactions. We aim to develop new approaches to this difficult problem, based on achieving a better understanding of what structural and physicochemical properties at protein-protein interfaces are important for inhibitor binding, and what kinds of novel chemical structures are best suited to exploit these features. Projects in this area are carried out in collaboration multiple other groups encompassing computational chemistry (Prof. Vajda), organic synthesis (Profs. Porco, Beeler, CMLD-BU; Prof. Pollastri, Northeastern U.), X-ray crystallography (Prof. Allen) and Biology (Prof. Gilmore, BU Department of Biology).
Techniques & Resources
Development and implementation of biochemical and cell-based assays using state-of-the art technologies such as FRET, Time-Resolved Fluorescence, and Fluorescence Polarization.
- the lab is equipped with a Biacore 3000 surface plasmon resonance (SPR) instrument for measuring protein-ligand binding in real time.
- fluorescence, analytical ultracentrifugation (AUC), dynamic lightscattering (DLS) and isothermal titration calorimetry (ITC)
- The lab has a dedicated Tissue Culture facility equipped with laminar flow biosafety cabinet, cell incubators, centrifuge, Nikon inverted microscope, and liquid nitrogen cell storage system.
- Specialized techniques for cell analysis (e.g. flow cytometry using a Becton-Dickinson FACSCaliburTM)
- Quantitative data analysis, curve fitting and reaction pathway modeling using a variety of software packages including site licenses to MathematicaTM and MatLab®.
What’s Next for Graduates of the Whitty Group?
The Whitty Group’s training in rigorous, hypothesis-driven experimental design and interpretation prepares students for future careers in either academia or industry.