Peter Wright, PhD

Structure, Dynamics and Interactions of Proteins.

My laboratory utilizes high-resolution nuclear magnetic resonance (NMR) spectroscopy and other biophysical and biochemical methods to investigate the structure, dynamics, and folding mechanisms of proteins and to map their functional interactions. NMR is unique as a method for determining three-dimensional structures of proteins and protein complexes in solution and also providing novel information about the time-dependent structural fluctuations that are essential for protein function.

Intrinsically disordered proteins and cellular signaling. Intrinsically disordered proteins are highly abundant in eukaryotes and play a central role in cellular regulatory processes and signaling pathways. We are using a multidisciplinary approach, including a broad range of biochemical and biophysical methods, NMR, and single molecule fluorescence (in collaboration with Ashok Deniz), to elucidate the structure of the general transcriptional coactivators CBP and p300 and the tumor suppressor p53 and characterize their functional interactions with key cellular and viral targets. We are implementing novel NMR methods, intein labeling technologies, and single molecule FRET methods to characterize the structure and dynamics of disordered proteins and their complexes and to elucidate the mechanism by which disordered proteins fold upon binding to their targets. 

Mechanisms of protein folding and misfolding. NMR is uniquely suited for studies of protein folding and misfolding pathways, providing detailed insights into the structure and dynamics of unfolded states and partially folded intermediates. We are applying NMR relaxation methods and real-time 19F NMR to elucidate the molecular mechanism by which the protein transthyretin spontaneously unfolds and aggregates, leading to amyloid disease.

Protein dynamics and "invisible" excited states. We are applying NMR relaxation dispersion methods to characterize the intrinsic dynamics of multivalent intrinsically disordered proteins when bound to their targets. Our goal is to characterize weakly populated excited states that modulate molecular interactions and play a functional role in biological switches..