Advertisement

Understanding the Specificity of the Dihydrofolate Reductase Binding Site

  • Gordon C. K. Roberts
Part of the NATO ASI Series book series (NSSA, volume 183)

Abstract

Recent developments in molecular and structural biology have transformed our ability to explore the structure-function relationships of biological macromolecules. This applies escpecially to the intermolecular interactions which form the basis of biological specificity. It is now possible to make precisely defined structural changes to each partner in these interactions, by genetic or chemical means, and the spectroscopic and crystallographic methods are available to assess the consequences of these changes in detail. As a result, it is now beginning to become possible to make quantitative estimates of the contributions of individual interactions to the overall molecular recognition process.

Keywords

Dihydrofolate Reductase Nuclear Overhauser Effect Conformational Isomer Negative Cooperativity Lineshape Analysis 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Andrews, J., Sims, P.F.G., Minter, S., and Davies, R. W., 1989a, submitted for publication.Google Scholar
  2. Andrews, J., Fierke, C.A., Birdsall, B., Ostler, G., Feeney, J., Roberts, G.C.K., and Benkovic, S.J., 1989b, A kinetic study of wild-type and mutant dihydrofolate reductases from Lactobacillus casei, Biochemistry 28:5743.CrossRefGoogle Scholar
  3. Antonjuk, D.J., Birdsall, B., Cheung, H.T.A., Clore, G.M., Feeney, J., Gronenborn, A.M., Roberts, G.C.K., and Tran, T.Q., 1984, A 1H NMR study of the role of the glutamate moiety in the binding of methotrexate to dihydrofolate reductase, Br. J. Pharmacol. 81:309.CrossRefGoogle Scholar
  4. Arnold, J.R.P., Tendier, S.J.B., Thomas, J.A., Birdsall, B., Feeney, J., and Roberts, G.C.K., 1989a, in preparation.Google Scholar
  5. Arnold, J.R.P., De Graw, J., Lian, L.-Y., and Roberts, G.C.K., 1989b, unpublished work.Google Scholar
  6. Bevan, A.W., Roberts, G.C.K., Feeney, J., and Kuyper, L., 1985, 1H and 15N NMR studies of protonation and hydrogen-bonding in the binding of trimethoprim to dihydrofolate reductase, Eur. J. Biophys. 11:211.CrossRefGoogle Scholar
  7. Birdsall, B., Burgen, A.S.V., and Roberts, G.C.K., 1980a, Binding of coenzyme analogues to Lactobacillus casei dihydrofolate reductase: Binary and ternary complexes, Biochemistry 19:3723.CrossRefGoogle Scholar
  8. Birdsall, B., Burgen, A.S.V., and Roberts, G.C.K. 1980b, Effects of coenzyme analogues on the binding of p-aminobenzoyl-L-glutamate and 2,4-diaminopyrimidine to Lactobacillus casei dihydrofolate reductase, Biochemistry 19:3732.CrossRefGoogle Scholar
  9. Birdsall, B., Burgen, A.S.V., Hyde, E.I., Roberts, G.C.K., and Feeney, J., 1981, Negative cooperativity between folinic acid and coenzyme in their binding to Lactobacillus casei dihydrofolate reductase, Biochemistry 20:7186.CrossRefGoogle Scholar
  10. Birdsall, B., Gronenborn, A.M., Hyde, E.I., Clore, G.M., Roberts, G.C.K., Feeney, J., and Burgen, A.S.V., 1982, 1H, 13C and 31P NMR studies of the dihydrofolate reductase-NADP-folate complex: Characterisation of three coexisting conformational states, Biochemistry 21:5831.CrossRefGoogle Scholar
  11. Birdsall, B., Bevan, A.W., Pascual, C., Roberts, G.C.K., Feeney, J., Gronenborn, A.M., and Clore, G.M., 1984, Multinuclear NMR characterisation of two coexisting conformational states of the Lactobacillus casei dihydrofolate reductase-trimethoprim-NADP+ complex, Biochemistry 23:4733.CrossRefGoogle Scholar
  12. Birdsall, B., De Graw, J., Feeney, J., Hammond, S.J., Searle, M.S., Roberts, G.C.K., Colwell, W.T., and Crase, J., 1987,15N and 1H NMR evidence for multiple conformations of the complex of dihydrofolate reductase with its substrate, folate, FEBS Lett. 217:106.CrossRefGoogle Scholar
  13. Birdsall, B., Andrews, J., Ostler, G., Tendier, S.J.B., Feeney, J., Roberts, G.C.K., Davies, R.W., and Cheung, H.T.A., 1989a, NMR studies of differences in the conformations and dynamics of ligand complexes formed with mutant dihydrofolate reductases, Biochemistry 28:1353.CrossRefGoogle Scholar
  14. Birdsall, B., Feeney, J., Tendier, S.J.B., Hammond, S.J., and Roberts, G.C.K., 1989b, Dihydrofolate reductase: multiple conformations and alternative modes of substrate binding, Biochemistry 28:2297.CrossRefGoogle Scholar
  15. Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C., and Kraut, J., 1982, Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 Å resolution, J. Biol. Chem. 257:13650.Google Scholar
  16. Cayley, P.J., Albrand, J.P., Feeney, J., Roberts, G.C.K., Piper, E.A., and Burgen, A.S.V., 1979, Nuclear magnetic resonance studies of the binding of trimethoprim to dihydrofolate reductase, Biochemistry 18:3886.CrossRefGoogle Scholar
  17. Charlton, P.A., Young, D.W., Birdsall, B., Feeney, J., and Roberts, G.C.K., 1979, Stereochemistry of reduction of folic acid using dihydrofolate reductase, J. Chem. Soc. Chem. Comm. 922.Google Scholar
  18. Charlton, P.A., Young, D.W., Birdsall, B., Feeney, J., and Roberts, G.C.K., 1985, Stereochemistry of the reduction of the vitamin folic acid by dihydrofolate reductase, J. Chem. Soc. Perkin I 1349.Google Scholar
  19. Cheung, H.T.A., Searle, M.S., Feeney, J., Birdsall, B., Roberts, G.C.K., Kompis, I., and Hammond, S.J., 1986, Trimethoprim binding to Lactobacillus casei dihydrofolate reductase: a 13C NMR study using selectively 13C-enriched trimethoprim, Biochemistry 25:1925.CrossRefGoogle Scholar
  20. Clore, G.M., Gronenborn, A.M., Birdsall, B., Feeney, J., and Roberts, G.C.K., 1984, 19F NMR studies of 3’5’-difluoremethotrexate biding to Lactobacillus casei dihydrofolate reductase. Molecular motion and coenzyme induced conformational change, Biochem. J. 217:659.Google Scholar
  21. Coceo, L., Groff, J.P., Temple, jr. C., Montgomery, J.A., London, R.E., Matwiyoff, N.A., and Blakley, R.A., 1981,13C NMR study of protonation of methotrexate and aminopterin bound to dihydrofolate reductase, Biochemistry 20:3972.CrossRefGoogle Scholar
  22. Feeney, J., Birdsall, B., Akiboye, J., Tendier, S.J.B., Barbero, J.J., Ostler, G., Arnold, J.R.P., Roberts, G.C.K., Kuhn, A., and Roth, K., 1989, Optimising selective deuteration of proteins for 2D 1H NMR detection and assignment studies: Application to the phenylalanine residues of dihydrofolate reductase, FEBS Letts., in press.Google Scholar
  23. Filman, D.J., Bolin, J.T., Matthews, D.A., and Kraut, J., 1982, Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 Å resolution II. J.Biol.Chem. 257:13663.Google Scholar
  24. Hammond, S.J., Birdsall, B., Searle, M.S., Roberts, G.C.K., and Feeney, J., 1986, Dihydrofolate reductase: 1H resonance assignments and coenzyme-induced conformational changes, J. Mol. Biol. 188:81.CrossRefGoogle Scholar
  25. Hammond, S.J., Birdsall, B., Feeney, J., Searle, M.S., Roberts, G.C.K., and Cheung, H.T.A., 1987, Structural comparisons of complexes of methotrexate analogues with L. casei dihydrofolate reductase by 2D 1H NMR at 500 MHz, Biochemistry 26:8585.CrossRefGoogle Scholar
  26. Hitchings, G.H., and Roth, B., 1980, Inhibition of dihydrofolate reductase, in: “Enzyme Inhibitors as Drugs,” M. Sandler, ed., Macmillan, London.Google Scholar
  27. Hood, K., and Roberts, G.C.K., 1978, Ultraviolet difference spectroscopic studies of substrate and inhibitor binding to Lactobacillus casei dihydrofolate reductase, Biochem. J. 171:357.Google Scholar
  28. Howell, E.E., Villafranca, J.E., Warren, M.S., Oatley, S.J., and Kraut, J., 1986, Functional role of aspartic acid 27 in dihydrofolate reductase revealed by mutagenesis, Sciewce 231:1123.ADSCrossRefGoogle Scholar
  29. Hyde, E.I., Birdsall, B., Roberts, G.C.K., Feeney, J., and Burgen, A.S.V., 1980a, Proton nuclear magnetic resonance saturation transfer studies of coenzyme binding to Lactobacillus casei dihydrofolate reductase, Biochemistry 19:3738.CrossRefGoogle Scholar
  30. Hyde, E.I., Birdsall, B., Roberts, G.C.K., Feeney, J., and Burgen, A.S.V., 1980b, Phosphorus-31 nuclear magnetic resonance studies of the binding of oxidised coenzymes to Lactobacillus casei dihydrofolate reductase, Biochemistry 19:3747.Google Scholar
  31. Gronenborn, A.M., Birdsall, B., Hyde, E.I., Roberts, G.C.K., Feeney, J., and Burgen, A.S.V., 1981, 1H and 31P NMR characterisation of two conformations of the trimethoprim-NADP+-dihydrofolate reductase complex, Mol. Pharmacol. 20:145.Google Scholar
  32. Jimenez, M.A., Arnold, J.R.P., Thomas, J.A., Roberts, G.C.K., Feeney, J., and Birdsall, B., 1989a, Dihydrofolate reductase: Control of the mode of substrate binding by aspartate 26, Protein Engineering 2:627.CrossRefGoogle Scholar
  33. Jimenez, M.A., Arnold, J.R.P., Thomas, J.A., G.C.K. Roberts, J. Feeney & B. Birdsall, 1989b, in preparation.Google Scholar
  34. Matthews, D.A., Bolin, J.T., Burridge, J.M., Filman, D.J., Volz, K.W., Kaufman, B.T., Beddell, C.R., Champness, J.N., Stammers, D.K., and Kraut, J., 1985, Refined crystal structures of Escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim, J. Biol. Chem. 260:381.Google Scholar
  35. Mayer, R.J., Chen, J.-T., Fierke, C.A., and Benkovic, S.J., 1986, Importance of a hydrophobic residue in binding and catalysis by dihydrofolate reductase, Proc. Natl. Acad. Sci. USA 83:7718.ADSCrossRefGoogle Scholar
  36. Oefner, C., D’Arcy, A., and Winkler, F.K., 1988, Crystal structure of human dihydrofolate reductase complexed with folate, Eur. J. Biochem. 174:377.CrossRefGoogle Scholar
  37. Roberts, G.C.K., Feeney, J., Burgen, A.S.V., and Daluge, S., 1981, The charge state of trimethoprim bound to Lactobacillus casei dihydrofolate reductase, FEBS Lett. 131:85.CrossRefGoogle Scholar
  38. Roth, B., and Cheng, C.C., 1982, Recent progress in the medicinal chemistry of 2,4-diaminopyrimidines, Prog. Med Chem. 19:270.Google Scholar
  39. Searle, M.S., Forster, M.J., Birdsall, B., Roberts, G.C.K., Feeney, J., Cheung, H.T.A., Kompis, I., and Geddes, A.J., 1988, The dynamics of trimethoprim bound to dihydrofolate reductase, Proc. Natl. Acad. Sci. USA 85:3787.ADSCrossRefGoogle Scholar
  40. Tendier, S.J.B., Griffin, R.J., Birdsall, B., Stevens, M.F.G., Roberts, G.C.K., and Feeney, J., 1988, Direct 19F NMR observation of the conformational selection of optically active rotamers of the antifolate compound fluoronitrophyrimethamine bound to the enzyme dihydrofolate reductase, FEBS Lett. 240:201.CrossRefGoogle Scholar
  41. Thomas, J.A., Andrews, J., Arnold, J.R.P., Roberts, G.C.K., Birdsall, B., and Feeney, J., 1989, unpublished work.Google Scholar
  42. Volz, K.W., Matthews, D.A., Alden, R.A., Freer, S.T., Hansch, C.T., Kaufman, B.T., and Kraut, J., 1982, Crystal structure of avian dihydrofolate reductase containing phenyltriazine and NADPH, J. Biol. Chem. 257:2528.Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Gordon C. K. Roberts
    • 1
  1. 1.Department of Biochemistry and Biological NMR CentreUniversity of LeicesterLeicesterUK

Personalised recommendations