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David Robert Shortle, M.D., Ph.D.
Professor of Biological Chemistry
Research Interests: Protein structure prediction; NMR characterization of unfolded proteins; Protein folding
Dr. David Robert Shortle is a professor of biological chemistry at the Johns Hopkins University School of Medicine. His research focuses on protein folding, nuclear magnetic resonance characterization of unfolded proteins and protein structure prediction.
Dr. Shortle received his B.S. in physics from Purdue University in 1970 and completed his M.D. and Ph.D. in biochemistry and molecular biology at Johns Hopkins in 1981. He then conducted a postdoctoral fellowship in biology at the Massachusetts Institute of Technology. After serving as an assistant professor of microbiology the State University of New York at Stony Brook School of Medicine, he joined the faculty of Johns Hopkins as an assistant professor of biological chemistry in 1984. He became an associate professor in 1987 and accepted the mantle of full professor in 1993.
Dr. Shortle serves on the editorial board of Current Opinion in Structural Biology. He has authored or co-authored approximately 100 peer-reviewed publications and holds one patent.
- Professor of Biological Chemistry
- Professor of Biophysics and Biophysical Chemistry
- M.D., Johns Hopkins University School of Medicine (Maryland) (1979)
- Ph.D., Johns Hopkins University School of Medicine (Maryland) (1979)
Massachusetts Institute of Technology, Cambridge, MA, 1982, Biology
Research & Publications
Dr. Shortle’s principal research interest is protein folding and stability: how amino acid sequence information encodes three-dimensional structure. The Shortle Lab combines experimental and computational approaches to study this longstanding puzzle of fundamental biochemistry. Several small proteins are being used as simple systems for characterizing the structure that persists in the unfolded (denatured) state, the starting point for folding both in the cell and in the test tube. In addition, the laboratory is working to predict protein structure from sequence in ways that make the underlying physical chemistry transparent and the relative contributions of different interactions quantifiable.
On the experimental side, the Shortle Lab uses staphylococcal nuclease and eglin C as simple systems for characterizing the residual structure that persists in the ensemble of conformations known as the denatured states. The lab uses several multi-dimensional NMR spectra collected on 15N and 13C labeled protein to assign all backbone resonances and identify protein segments that retain partial helix, strand, or turn structure. Through paramagnetic relaxation enhancement, the lab can define the three-dimensional topology of the denatured state and residual dipolar couplings are tracked as a function of solution conditions to monitor the change in this topology. The most important conclusion reached to date is that a native-like topology persists for both proteins, even at high concentrations of urea. This has led to a current working assumption that local side chain-backbone interactions, not long-range hydrophobic contacts, are responsible for this structure.
Shortle D. "One sequence plus one mutation equals two folds." Proc Natl Acad Sci USA. 2009. 106: 21011-21012.
Shortle D. "The Denatured States of Proteins: How Random Are They?" In Unfolded Proteins, Trevor Creamer, editor. Nova Science Publishers, Inc., New York. 2008.
Gebel, E. and Shortle, D. "Characterization of denatured proteins using residual dipolar couplings." Methods in Molecular Biology. 2007. 350: 39-48.
Ohnishi S, Kamikubo H, Onitsuka M , Kataoka M, and Shortle D. "Conformational preference of polyglycine in solution for elongated structures." Submitted to J Am Chem Soc. 2006. 128:16338-16344.
Gebel, E. Ruan, K.; Tolman, J.R and Shortle, D. "Multiple alignment tensors from a denatured protein." J. Am. Chem. Soc. 2006. 128: 9310-9311.
Academic Affiliations & Courses
Graduate Program Affiliation
Program in Molecular Biophysics