个人简介

BS/MS 1994, Utah State University, PhD 2000, University of California at Berkeley, NIH Postdoctoral Fellowship, 2002-2005, Sunesis Pharmaceuticals

研究领域

Identification and exploitation of allosteric sites/Biomedically important proteases/Structural biology/Drug design/Neurodegenerative Diseases

Many biological responses are triggered when small chemical moieties bind to cavities or surfaces of proteins. Attention typically focuses on small molecules binding to the main functional site, which is termed the protein active site. In other cases, binding of small molecules to external sites, called allosteric sites, dramatically influences the activity of the protein. Some well known allosteric sites like those in hemoglobin, citrate synthase and glycogen phosphorylase were discovered many years ago; however, new allosteric sites like the one in caspase-7 (right, red) are being uncovered serendipitously all the time. We aim to understand and exploit allosteric regulation by designing allosteric binding sites for alternative small molecules. We redesign both known and novel allosteric sites to be controlled by the small molecule of our choice. In the figure at the right a novel allosteric site cavity in caspase-7 (red) is occupied by a small molecule we chose based on its size, solubility and exceptional drug-like properties (yellow sticks). Redesigning this novel allosteric site to bind to an alternative small molecule will allow us to regulate caspase-7 activity independently of all other caspases.

近期论文

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Caspase Papers Velazquez-Delgado, E. M. and Hardy, J. A., 2012. "Zinc-Mediated Allosteric Inhibition of Caspase-6."Journal of Biological Chemistry. 287(43), 36000. Huber, K.L. and Hardy J.A., 2012 "Mechanism of zinc-mediated inhibition of caspase-9." Protein Science. 21,1056-1065.. Article featured as cover illustration. pdf Huber, K.L., Ghosh, S. and Hardy J.A., 2012. "Inhibition of caspase-9 by stabilized peptides targeting the dimerization interface."Peptide Science. 98(5), 451–465. pdf Velazquez-Delgado, E. M. and Hardy J.A., 2012. "Phosphorylation regulates assembly of the caspase-6 substrate-binding groove." Structure. 20, 742–751. pdf; preview; press release Vaidya S., Hardy J.A., Caspase-6 Latent State Stability Relies on Helical Propensity. Biochemistry 2011, 50(16):3282-7. pdf Vaidya S., Velázquez-Delgado E.M., Abbruzzese G., Hardy J.A. Substrate-Induced Conformational Changes Occur in All Cleaved Forms of Caspase-6. Journal of Molecular Biology 2011, 406(1):75-91. pdf Witkowski, W.A., Hardy, J.A. "L2 loop is critical for caspase-7 active site formation" Protein Science, 2009, 18, 1459-1468. Article featured as cover illustration. Witold's movie of conformational changes in the capsase mutant I213A. Hardy, J. A. and Wells, J. "Dissecting an Allosteric Switch in Caspase-7 using Chemical and Mutational Probes." Journal Biological Chemistry 2009, 284(38):26063-9. pdf Hardy, J. A., Lam, J., Nguyen, J. T., O’Brien, T. and Wells, J. "Discovery of an allosteric site in caspases." Proc. Natl. Acad. Sci. U S A. 2004, 101(34), 12461-6. pdf movie Protein Design Papers Wu, P., Nicholls, S., and Hardy, J.A. 2013 "A tunable, modular approach to fluorescent protease-activated reporters." in Press Biophysical Journal. Nicholls, S. and Hardy, J.A. 2013 "Structural Basis of Fluorescence Quenching in Caspase Activatable-GFP." Protein Science. 22(3), 247. Article featured as cover illustration. López, G.E, Colón-Díaz, I., Cruz, A., Ghosh,S., Nicholls, S.B., Viswanathan, U., Hardy, J.A. and Auerbach, S.M. 2012 "Modeling non-aqueous proton wires tethered to helical peptides: Biased proton transfer driven by helical dipoles." The Journal of Physical Chemistry A. 116(4):1283-8. pdf Nicholls, S., Chu, J., Abbruzzese, G. Tremblay, K.D. and Hardy, J.A. "Mechanism of a dark-to- bright reporter of caspase activity."Journal of Biological Chemistry, 286 (28), 24977-24986. pdf; press release CA-GFP Movie Witkowski, W. and Hardy, J.A. "A designed redox-controlled caspase"Protein Science, 20, 1421-1431. Article featured as cover illustration. Huber, K.L., Olson, K.D. and Hardy, J.A. "Robust production of a peptide library using methodological synchronization" Protein Expression and Purification. 2009, 67,139-147. pdf Hardy, J. A. and Nelson, H. C. M. "Proline in an alpha-helical kink is required for folding kinetics but not for kinked structure, function or stability of heat shock transcription factor" Protein Science, 2000, 9(11), 2128-2141. pdf Hardy, J. A., Walsh, S. T. R., and Nelson, H. C. M. "Role of an alpha-Helical Bulge in the Yeast Heat Shock Transcription Factor" J. Mol. Biol., 2000, 295(3), 393-409.