From Structure to Therapy?

  • L. N. Johnson


Protein crystal structure determinations have made important contributions to understanding the molecular basis of recognition and function. In some selected examples, protein structures have been used to design new therapeutic agents. This paper summarises recent achievements and reports on progress in our long term study to provide potential agents for the treatment of diabetes. Structural studies with glycogen phosphorylase have led to the design of a series of glucose analogue inhibitors that can act as powerful regulators of liver glycogen metabolism. The best compound to date has involved some novel carbohydrate chemistry and exhibits a Ki that is 3 orders of magnitude lower than that of glucose. Physiological studies have shown that inhibitors more potent than glucose produce dramatic effects in inhibition of glycogen degradation and promotion of increased glucose utilisation and glycogen deposits in isolated hepatocytes.


Glycogen Phosphorylase Glycogen Metabolism Purine Nucleoside Phosphorylase Structure Base Drug Design Glycogen Degradation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Picot, D., Loll, P. J. and Garavito, M. (1994) Nature367: 243–249.PubMedCrossRefGoogle Scholar
  2. 2.
    Vagelos, P. R. (1991) Science252: 1080–1084.CrossRefGoogle Scholar
  3. 3.
    Perutz, M. F. (1992). Protein Structure: New approaches to disease and therapy. W. H. Freeman, New York.Google Scholar
  4. 4.
    Goodford, P. J. (1985) J. Med. Chem.28: 849–857.PubMedCrossRefGoogle Scholar
  5. 5.
    Von Itzstein, M., Wu, W.-Y., Kok, G. B., Pegg, M. S., Dyasson, J. C., Jin, B., Phan, T. V., Smythe, M. L., White, H. F., Oliver, S. W., Colman, P. M., Varghese, J. N., Ryan, D. M., Woods, J. M., Bethell, R. C., Hothmam, V. J., Cameron, J. M. and Penn, C. R. (1993) Nature 363: 418–423.CrossRefGoogle Scholar
  6. 6.
    Lam, P. Y. S., Jadhav, P. K., Eyermann, C. J., Hodge, C. N., Ru, Y., Bacheler, L. Y., Meek, J. L., Otto, M. J., Rayner, M. M.J., Wong, Y., N„ Chang, C.-W., Weber, P. C., Jackson, D. A., Sharpe, T. R. and Erickson-Viitanen, S. (1994) Science 263: 380–384.PubMedCrossRefGoogle Scholar
  7. 7.
    Montgomery, J. A., Niwas, S., Rose, J. D., Secrist, J. A., Babu, Y. S., Bugg, C. E., Erion, M. D., Guida, W. C. and Ealick, S. E. (1993) J. Med. Chem.36: 55–69.PubMedCrossRefGoogle Scholar
  8. 8.
    Reich, S. H., Fuhry, M. A. M., Nguyen, D., Pino, M. J., Welsh, K. M., Webber, S., Janson, C. A., Jordan, S. R., Matthews, D. A., Smith, W. W., Bartlett, C. A., Booth, C. L. J., Herrmann, S. M., Howland, E. F., Morse, C. A., Ward, R. W. and White, J. (1992) J. Med. Chem.35: 847–858.PubMedCrossRefGoogle Scholar
  9. 9.
    DeFronzo, R. A. (1988) Diabetes 37: 667–687.PubMedGoogle Scholar
  10. 10.
    Hers, H. G. (1976) Ann. Rev. Biochem.45: 167–189.PubMedCrossRefGoogle Scholar
  11. 11.
    Stalmans, W. (1976) Curr. Topics Cell Reg.11: 51–97.Google Scholar
  12. 12.
    Dent, P., Lavoinne, A., Nakielny, S., Caudwell, F. B., Watt, P. and Cohen, P. (1990) Nature 348: 302–308.PubMedCrossRefGoogle Scholar
  13. 13.
    Allemany, S. and Cohen, P. (1986) FEBS Lett. 198: 194-.CrossRefGoogle Scholar
  14. 14.
    Wera, S., Bollen, M. and Stalmans, W. (1991) J Biol. Chem.266: 339.PubMedGoogle Scholar
  15. 15.
    Witters, L. A. and Avruch, J. (1978) Biochemistry 17: 406–410.PubMedCrossRefGoogle Scholar
  16. 16.
    Sprang, S. R., Goldsmith, E. J., Fletterick, R. J., Withers, S. G. and Madsen, N. B. (1982) Biochemistry 21: 5364–5371.PubMedCrossRefGoogle Scholar
  17. 17.
    Martin, J. L., Withers, S. G. and Johnson, L. N. (1990) Biochemistry 29: 10745–10757.PubMedCrossRefGoogle Scholar
  18. 18.
    Barford, D. and Johnson, L. N. (1989) Nature 340: 609–614.PubMedCrossRefGoogle Scholar
  19. 19.
    Acharya, K. R., Stuart, D. I., Varvill, K. M. and Johnson, L. N. (1991). Glycogen phosphorylase: Description of the protein structure. World Scientific, London and Singapore.Google Scholar
  20. 20.
    Barford, D., Hu, S.-H. and Johnson, L. N. (1991) J. Mol. Biol.218: 233–260.PubMedCrossRefGoogle Scholar
  21. 21.
    Johnson, L. N. (1992) FASEB J. 6: 2274–2282.PubMedGoogle Scholar
  22. 22.
    Johnson, L. N. and Barford, D. (1993) Annu. Rev. Biophys. Biomol. Struct.22: 199–232.PubMedCrossRefGoogle Scholar
  23. 23.
    Johnson, L. N. and Barford, D. (1994) Protein Sci. 3: 1726–1730.PubMedCrossRefGoogle Scholar
  24. 24.
    Martin, J. L., Veluraja, K., Ross, K., Johnson, L. N., Fleet, G. W. J., Ramsden, N. G., Bruce, I., Orchard, M. G., Oikonomakos, N. G., Papageorgiou, A. C., Leonidas, D. D. and Tsitoura, H. S. (1991) Biochemistry 30: 10101–10116.PubMedCrossRefGoogle Scholar
  25. 25.
    Johnson, L. N., Watson, K. A., Mitchell, E. P., Fleet. G. W. J., Son, J. C., Bichard, C. J. F., Oikonomakos, N. G., Papageorgiou, A. C. and Leonidas, D. D. (1994) Complex carbohydrates in drug research: (Bock, K. and Claussen, H. eds.) pp. 214–226, Copenhagen, Munksgaard.Google Scholar
  26. 26.
    Watson, K. A., Mitchell, E. P., Johnson, L. N., Son, J. C., Bichard, C. J. F., Orchard, M. G., Fleet, G. W. J., Oikonomakos, N. G., Leonidas, D. D., Kontou, M. and Papageorgiou, A. C. (1994) Biochemistry33: 5745–5758.PubMedCrossRefGoogle Scholar
  27. 27.
    Bichard, C. J. F., Mitchell, E. P., Wormald, M. R., Watson, K. A., Johnson, L. N., Zographos, S. E., Koutra, D. D., Oikonomakos, N. G. and Fleet, G. W. J. (1995) Tetrahedron Letts. In pressGoogle Scholar
  28. 28.
    Watson, K. A., Mitchell, E. P., Johnson, L. N., Crucianni, G., Son, J. C., Bichard, C. J. F., Fleet, G. W. J., Oikonomkos, N. G., Leonidas, D. D. and Kontou, M. (1995) Acta Cryst. D In pressGoogle Scholar
  29. 29.
    Watson, K. A., Mitchell, E. P., Johnson, L. N., Son, Y., Fleet, G. W. J. and Oikonomakos, N. G. (1993) J. Chem. Soc. Chem. Commun.654–656.Google Scholar
  30. 30.
    Board, M., Hadwen, M. and Johnson, L. N. (1995). Eur. J. Biochem. In press.Google Scholar

Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • L. N. Johnson
    • 1
  1. 1.Laboratory of Molecular BiophysicsUniversity of OxfordOxfordUK

Personalised recommendations