The use of NMR Spectroscopy to Probe the Relationship Between Protein Structure and Disease:

I am interested in understanding how the three-dimensional structure of proteins and nucleic acids controls their biological function. Changes in the chemical composition of a protein, perhaps through a spontaneous mutation can disrupt its structure which may dramatically interfere with its normal function. This in turn can lead to the development of diseases such as cancer. Understanding the fine balance between structure and function and how these correlate with the onset of disease is one of the major challenges for pharmacologists and biochemists today. If we can find out how the structure of a molecule defines its biological function we can begin to design new pharmaceutical drugs for fighting disease. Research in my lab uses Nuclear Magnetic Resonance (NMR) spectroscopy to study the structure and dynmaics of biological molecules implicated in the development and progression of disease. NMR spectroscopy is used to solve the three dimensional structures of molecules in solution. However this is only the first step in understanding structure-function relationships in proteins. NMR is one of the only techniques that can provide information about how flexibility of a protein contributes to its function. As an example, many proteins change their structure on binding to a drug or other ligand. Understanding the dynamics was an important part of the design of HIV protease inhibitors for the treatment of AIDS patients. My laboratory uses NMR to probe the contributions that dynamic processes make to understanding the function of proteins.

Education / Experience

• Undergraduate Thesis Project, University of Bristol, U.K.1986
  Synthesized and performed biological tests on plant growth hormones.
• Ph.D. Research, University of Cambridge, U.K., with Dr. Jeremy Sanders1986-1989
  Developed NMR methods to determine structures of intact capsular polysaccharides from pathogenic bacteria.
• Postdoctoral Research, University of Cambridge, U.K. , with Prof. Alan Fersht1989-1992
  Mapped the inhibitor binding site of a ribonuclease by multidimensional NMR techniques.
• Postdoctoral Research Associate, MRC Laboratory of Molecular Biology, Cambridge, U.K. with Dr. David Neuhaus1992-1995
  Solved the NMR solution structure of the chromosomal protein HMG-D and mapped its interactions with DNA.
• Research Associate, University of Chicago, Chicago, IL, Department of Biochemistry and Molecular Biology1995-1997 Assistant Manager of the Biological Sciences Divisional NMR Facility.
  Solved the structure of the C-terminal subunit of an RNA polymerase and the structures of beta-amyloid peptides involved in the development of alzheimer's disease.
• Assistant Professor, Department of Pharmacology, University of Colorado Health Sciences Center, Denver CO.1997-Present
  Initiated an independent research program applying high field NMR spectroscopy to study the molecular basis of alcohol specificity inalcohol binding proteins.

Professional Activities

• American Heart Association-Southwestern Division1999
  Ad-Hoc Reviewer for Structural Biology Grants

Bibliography

1. Fowles, A.M., Beale, M.H., Jones, D.N.M., Macmillan, J., and Willis,
   C.L., (1988) "2-Alpha-Alkyl Gibberellin-A1 and Gibberellin-A4.", J. Chem. Soc.-Perkin Trans. 1, 1983-1991.

2. Cavanagh, J., Hunter, C.A., Jones, D.N.M., Keeler, J., and Sanders,
   J.K.M., (1988) "Practicalities and Applications of Reverse Heteronuclear Shift Correlation - Porphyrin and Polysaccharide Examples.", Magn. Reson. Chem., 26, 867-875.

3. Jones, D.N.M. and Sanders, J.K.M., (1989) "Assignment of the C-13
   NMR-Spectrum of the Klebsiella K3 Serotype Polysaccharide By Cosy
   Spectroscopy.", J. Chem. Soc.-Chem. Commun., 167-169.

4. Jones, D.N.M. and Sanders, J.K.M., (1989) "Biosynthetic-Studies Using C-13 Cosy - the Klebsiella K3- Serotype Polysaccharide.", J. Amer. Chem. Soc., 111, 5132-5137

5. Jones, D.N.M. and Sanders, J.K.M., (1990) "A Reverse Approach to
   H-1-NMR Assignments of Bacterial Polysaccharides.", Carbohydr. Res., 208, 15-21.

6. Jones, D.N.M., Bycroft, M., Lubienski, M.J., and Fersht, A.R., (1993)
   "Identification of the Barstar Binding-Site of Barnase By NMR- Spectroscopy and Hydrogen-Deuterium Exchange.", FEBS Lett., 331, 165-172.

7. Lubienski, M.J., Bycroft, M., Jones, D.N.M., and Fersht, A.R., (1993)
   "Assignment of the Backbone H-1 and N-15 Nmr Resonances and Secondary Structure Characterization of Barstar.", FEBS Lett., 332, 81-87.

8. Jones, D.N.M., Searles, M.A., Shaw, G.L., Churchill, M.E.A., Ner,
   S.S., Keeler, J., Travers, A.A., and Neuhaus, D., (1994) "The Solution
   Structure and Dynamics of the DNA-Binding Domain of HMG-D From
   Drosophila-Melanogaster.", Structure, 2, 609-627.

9. Churchill, M.E.A., Jones, D.N.M., Glaser, T., Hefner, H., Searles,
   M.A., and Travers, A.A., (1995) "HMG-D Is an Architecture-Specific Protein That Preferentially Binds to Dna Containing the Dinucleotide TG.", EMBO J., 14, 1264-1275.

10. Fletcher, C.M., Jones, D.N.M., Diamond, R., and Neuhaus, D., (1996)
    "Treatment of NOE constraints involving equivalent or nonstereoassigned protons in calculations of biomacromolecular structures.", J. Biomol. NMR, 8, 292-310.

11. Wang, B., Jones, D.N.M., Kaine, B.P., and Weiss, M.A., (1998)
    "High-resolution structure of an archaeal zinc ribbon defines a general
    architectural motif in eukaryotic RNA polymerases.", Struct. Fold. Dec., 6, 555-569.

12. Burkoth, T.S., Benzinger, T.L.S., Jones, D.N.M., Hallenga, K.,
    Meredith, S.C., and Lynn, D.G., (1998) "C-terminal PEG blocks the
    irreversible step in beta-amyloid(10- 35) fibrillogenesis.", J. Amer. Chem. Soc., 120, 7655-7656.

13. Benzinger, T.L.S., Jones, D.N.M., et al., (1998) "Structure-function relationships in side chain lactam cross- linked peptide models of a conserved N-terminal domain of apolipoprotein E.", Biochemistry, 37, 13222-13229.

14. Jones, D.N.M. and Bendiak, B., (1999) "Novel multi-dimensional
    heteronuclear NMR techniques for the study of 13C-O-acetylated
    oligosaccharides: Expanding the dimensions for carbohydrate structures.", J. Biomol. NMR, 15, 157-168.

15. Dow, L.K., Jones, D.N.M., Wolfe, S.A., Verdine, G.L., and Churchill,
    M.E.A., (2000) "Structural studies of the high mobility group globular
    domain and basic tail of HMG-D bound to disulfide cross-linked DNA.", Biochemistry, 39, 9725-9736.

16. Bendiak, B., Fang, T.T., and Jones, D.N.M., (2002) "New methods in
    nuclear magnetic resonanance/derivatization tailored to oligosaccharide structural elucidation: application to glycoprotein oligosaccharides.", Can. J. Chem, (in press).