Skip to main content
SpringerLink
Log in

From Structure to Therapy?

  • Chapter
Protein Structure — Function Relationship

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Picot, D., Loll, P. J. and Garavito, M. (1994) Nature367: 243–249.

    Article  PubMed  CAS  Google Scholar 

  2. Vagelos, P. R. (1991) Science252: 1080–1084.

    Article  Google Scholar 

  3. Perutz, M. F. (1992). Protein Structure: New approaches to disease and therapy. W. H. Freeman, New York.

    Google Scholar 

  4. Goodford, P. J. (1985) J. Med. Chem.28: 849–857.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  9. DeFronzo, R. A. (1988) Diabetes 37: 667–687.

    PubMed  CAS  Google Scholar 

  10. Hers, H. G. (1976) Ann. Rev. Biochem.45: 167–189.

    Article  PubMed  CAS  Google Scholar 

  11. Stalmans, W. (1976) Curr. Topics Cell Reg.11: 51–97.

    CAS  Google Scholar 

  12. Dent, P., Lavoinne, A., Nakielny, S., Caudwell, F. B., Watt, P. and Cohen, P. (1990) Nature 348: 302–308.

    Article  PubMed  CAS  Google Scholar 

  13. Allemany, S. and Cohen, P. (1986) FEBS Lett. 198: 194-.

    Article  Google Scholar 

  14. Wera, S., Bollen, M. and Stalmans, W. (1991) J Biol. Chem.266: 339.

    PubMed  CAS  Google Scholar 

  15. Witters, L. A. and Avruch, J. (1978) Biochemistry 17: 406–410.

    Article  PubMed  CAS  Google Scholar 

  16. Sprang, S. R., Goldsmith, E. J., Fletterick, R. J., Withers, S. G. and Madsen, N. B. (1982) Biochemistry 21: 5364–5371.

    Article  PubMed  CAS  Google Scholar 

  17. Martin, J. L., Withers, S. G. and Johnson, L. N. (1990) Biochemistry 29: 10745–10757.

    Article  PubMed  CAS  Google Scholar 

  18. Barford, D. and Johnson, L. N. (1989) Nature 340: 609–614.

    Article  PubMed  CAS  Google Scholar 

  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. Barford, D., Hu, S.-H. and Johnson, L. N. (1991) J. Mol. Biol.218: 233–260.

    Article  PubMed  CAS  Google Scholar 

  21. Johnson, L. N. (1992) FASEB J. 6: 2274–2282.

    PubMed  CAS  Google Scholar 

  22. Johnson, L. N. and Barford, D. (1993) Annu. Rev. Biophys. Biomol. Struct.22: 199–232.

    Article  PubMed  CAS  Google Scholar 

  23. Johnson, L. N. and Barford, D. (1994) Protein Sci. 3: 1726–1730.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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 press

    Google Scholar 

  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 press

    Google Scholar 

  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. Board, M., Hadwen, M. and Johnson, L. N. (1995). Eur. J. Biochem. In press.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Molecular Biophysics, University of Oxford, Oxford, OX1 3QU, UK

    L. N. Johnson

Authors
  1. L. N. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. H. E. J. Research Institute of Chemistry, University of Karachi, Karachi, Pakistan

    Zafar H. Zaidi

  2. Department of Chemistry, University of Nebraska, Lincoln, Nebraska, USA

    David L. Smith

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Plenum Press, New York

About this chapter

Cite this chapter

Johnson, L.N. (1996). From Structure to Therapy?. In: Zaidi, Z.H., Smith, D.L. (eds) Protein Structure — Function Relationship. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0359-6_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-4613-0359-6_11

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-8015-3

  • Online ISBN: 978-1-4613-0359-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation