The Skaggs Institute for Chemical Biology
Faculty, Graduate Program
Adjunct Professor, The Salk Institute
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 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 of disordered proteins and their complexes and to elucidate the mechanism by which disordered proteins fold upon binding to their targets.
Mechanisms of nucleic acid recognition by zinc finger proteins. We are using NMR and X-ray crystallography (in collaboration with Ian Wilson's laboratory) to elucidate the structural basis by which the protein Muscleblind recognizes pathogenic RNA sequences, and by which the protein Kaiso binds both regulatory and methylated DNA motifs.
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 dispersion methods 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 dynamics of the enzyme dihydrofolate reductase and to determine the structure of weakly populated excited states that play a functional role in catalysis. These studies, which are also being applied to study the dynamics of a stress-activated protein kinase, are providing unprecedented insights into the intrinsic dynamics of enzymes and their role in catalysis.
B.Sc., Chemistry, University of Auckland, 1968
M.Sc., Chemistry, University of Auckland, 1969
Ph.D., Chemistry, University of Auckland, 1972
The Scripps Research Institute, 1984-present, Professor
The Scripps Research Institute, 1987-2012, Chair, Department of Molecular Biology
University of Sydney, 1976-1984, Lecturer/Senior Lecturer, Department of Inorganic Chemistry
University of Oxford, 1972-76, Postdoctoral, Chemistry/Biochemistry
Member of the National Academy of Sciences, 2008
Fellow of the American Academy of Arts and Sciences, 1995
Honorary Doctor of Science, The University of Sydney, Australia, 2003
Honorary Doctorate in Medicine, Karolinska Institute, Stockholm, 1995
American Chemical Society, San Diego Section, Distinguished Scientist Award, 2010
The Stein and Moore Award, The Protein Society, 2010
Honorary Member, Israel Chemical Society, 2009
Fellow, International Society of Magnetic Resonance, 2008
Leach Medal, 2008
Honorary Member, NMR Society of Japan, 2006
Fellow, American Association for the Advancement of Science, 1998
NIH Merit Award, 1994-2001
Editor-in-Chief, Journal of Molecular Biology
Editorial Boards: Biochemistry, Current Opinion in Structural Biolgy, Journal of Biomolecular NMR
The dynamic energy landscape of dihydrofolate reductase catalysis. D.D. Boehr, D. McElheny, H.J. Dyson and P.E. Wright (2006), Science 313, 1638-1642.
Mechanism of coupled folding and binding of an intrinsically disordered protein. K. Sugase, H.J. Dyson and P.E. Wright (2007), Nature 447, 1021-1027.
Measurement of protein unfolding/refolding kinetics and structural characerization of hidden intermediates by NMR relaxation dispersion. D.W. Meinhold, P.E. Wright (2011), Proc. Natl Acad. Sci., 108, 9078-9083.
Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso. B.A. Buck-Koehntop, R.L. Stanfield, D.C. Ekiert, M.A. Martinez-Yamout, H.J. Dyson, I.A. Wilson and P.E. Wright (2012), Proc. Natl Acad. Sci., 109, 15229-15234.
Modulation of allostery by protein intrinsic disorder. A.C.M. Ferreon, J.C. Ferreon, P.E. Wright, A.A. Deniz (2013), Nature, 498, 390-394.