Advertisement

NMR-Based Strategies to Elucidate Bioactive Conformations of Weakly Binding Ligands

  • Marcel J. J. BlommersEmail author
  • Andre Strauss
  • Martin Geiser
  • Paul Ramage
  • Helmut Sparrer
  • Wolfgang Jahnke
Chapter
  • 807 Downloads
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 273)

Abstract

Key processes in molecular biology are regulated by interactions between biomolecules. Protein–proteinand protein–ligand interactions, e.g., in signal transduction pathways, rely on the subtle interactionsbetween atoms at the binding interface of the involved molecules. Because biomolecules often havemany interacting partners, these interactions are not necessarily strong. The study of molecularrecognition gives insight into the complex network of signaling in life and is the basis of structure-baseddrug design.

In the situation where the interaction is weak, one of the traditional methods that can be appliedto obtain structural information (internuclear distances) of the bound ligand is the so-called transferredNOE (trNOE) method. Recently, it became possible to use transferred cross-correlated relaxation (trCCR)to directly measure dihedral angles. The combined use of these two techniques significantly improvesthe precision of the structure determination of ligands weakly bound to macromolecules.

The application of these techniques will be discussed in detail for a peptide derived fromIKKβ bound to the protein NEMO that plays an important rolein the NFκB pathway.

Cross-correlated relaxation IKKβ NEMO NMR trCCR trNOE 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Macura S, Ernst RR (1980) Mol Phys 41:95 CrossRefGoogle Scholar
  2. 2.
    Neuhaus D, Williamson M (1989) The Nuclear Overhauser Effect in Structural and Conformational Analysis. VCH Publishers, New York Google Scholar
  3. 3.
    Karplus M (1959) J Chem Phys 30:11 CrossRefGoogle Scholar
  4. 4.
    Bystrov VF (1976) Prog NMR Spect 10:41 CrossRefGoogle Scholar
  5. 5.
    Wüthrich K (1986) NMR of Proteins and Nucleic Acids. Wiley, New York Google Scholar
  6. 6.
    Tjandra N, Omichinski JG, Gronenborn AM, Clore GM, Bax A (1997) Nat Struct Biol 4:732 CrossRefGoogle Scholar
  7. 7.
    Reif B, Hennig M, Griesinger C (1997) Science 276:1230 CrossRefGoogle Scholar
  8. 8.
    Carlomagno T, Felli IC, Czech M, Fischer R, Sprinzi M, Griesinger C (1999) J Am Chem Soc 121:1945 CrossRefGoogle Scholar
  9. 9.
    Blommers MJJ, Stark W, Jones CE, Head D, Owen CE, Jahnke W (1999) J Am Chem Soc 121:1949 CrossRefGoogle Scholar
  10. 10.
    Dalvit C, Bodenhausen G (1988) J Am Chem Soc 110:7924 CrossRefGoogle Scholar
  11. 11.
    Dalvit C, Bodenhausen G (1990) Adv Magn Res 14:1 CrossRefGoogle Scholar
  12. 12.
    Feng X, Lee YK, Sandström S, Eden M, Maisel H, Sebald A, Levitt MH (1996) Chem Phys Lett 257:314 CrossRefGoogle Scholar
  13. 13.
    Feng X, Verdegem PJE, Lee YK, Sandström D, Eden M, Bovee-Geurts P, de Grip WJ, Lugtenburg J, de Groot HJM, Levitt MH (1997) J Am Chem Soc 119:6853 CrossRefGoogle Scholar
  14. 14.
    Schmidt-Rohr K (1996) J Am Chem Soc 118:7601 CrossRefGoogle Scholar
  15. 15.
    Cavanagh J, Fairbrother WJ, Palmer AG III, Skelton NJ (1996) Protein NMR Spectroscopy. Academic Press, San Diego, p 265 Google Scholar
  16. 16.
    Reif B, Diener A, Henning M, Maurer M, Griesinger C (2000) J Magn Res 143:45 CrossRefGoogle Scholar
  17. 17.
    Tessari M, Vis H, Boelens R, Kaptein R, Vuister G (1997) J Am Chem Soc 119:8985 CrossRefGoogle Scholar
  18. 18.
    Yang D, Konrat R, Kay LE (1997) J Am Chem Soc 119:11938 CrossRefGoogle Scholar
  19. 19.
    Ni F (1994) Progr NMR Spectros 26:517 CrossRefGoogle Scholar
  20. 20.
    Lian LY, Barsukov IL, Sutcliffe MJ, Sze KH, Roberts GCK (1994) Methods Enzymol 239:657 CrossRefGoogle Scholar
  21. 21.
    Campbell AP, Sykes BD (1993) Annu Rev Biophys Biomol Struct 22:99 CrossRefGoogle Scholar
  22. 22.
    Blommers MJJ, Rüdisser S (2002) BioNMR in drug research. In: Zerbe E (ed) Methods and Principles in Medicinal Chemistry. Wiley-VCH, Weinheim, Germany, p 355 Google Scholar
  23. 23.
    Felli IC, Richter C, Griesinger C, Schwalbe H (1999) J Am Chem Soc 121:1956 CrossRefGoogle Scholar
  24. 24.
    Höfle G, Bedorf N, Gerth K, Reichenbach H (1993) Chem Abstr 120:52841 Google Scholar
  25. 25.
    Nicolau KC, Roschangar F, Vourlominis D (1998) Angew Chem Int Ed 37:2014 CrossRefGoogle Scholar
  26. 26.
    Wartmann M, Altmann K-H (2002) Curr Med Chem Anti-Cancer Agents 2:123 CrossRefGoogle Scholar
  27. 27.
    Carlomagno T, Blommers MJJ, Meiler J, Jahnke W, Schupp T, Petersen F, Schinzer D, Altmann K-H, Griesinger C (2003) Angew Chem Int Ed 42:2511 CrossRefGoogle Scholar
  28. 28.
    Carlomagno T (2005) Ligand-target interactions: what can we learn from NMR? Annu Rev Biophys Biomol Struct 34:245 CrossRefGoogle Scholar
  29. 29.
    Carlomagno T, Sanchez VM, Blommers MJJ, Griesinger C (2003) Angew Chem 42:2515 CrossRefGoogle Scholar
  30. 30.
    Mizukoshi Y, Takahashi H, Shimada I (2006) J Biomol NMR 34:23 CrossRefGoogle Scholar
  31. 31.
    Karin M, Yamamoto Y, Wang QM (2004) Nat Rev Drug Discov 3:17 CrossRefGoogle Scholar
  32. 32.
    May MJ, D’Acquisto F, Madge LA, Glockner J, Pober JS, Ghosh S (2000) Science 289:1550 CrossRefGoogle Scholar
  33. 33.
    May MJ, Marienfeld RB, Ghosh S (2000) J Biol Chem 27:45992 Google Scholar
  34. 34.
    Agou F, Courtois G, Chiaravalli J, Baleux F, Coic YM, Traincard F, Israel A, Veron M (2004) J Biol Chem 279:54248 CrossRefGoogle Scholar
  35. 35.
    Choi M, Rolle S, Wellner M, Cardoso MC, Scheidereit C, Luft FC, Kettritz R (2003) Blood 102:2259 CrossRefGoogle Scholar
  36. 36.
    Tas SW, de Jong EC, Hajji N, May MJ, Ghosh S, Vervoordeldonk MJ, Tak PP (2005) Eur J Immunol 35:1164 CrossRefGoogle Scholar
  37. 37.
    Dai S, Hirayama T, Abbas S, Abu-Amer Y (2004) J Biol Chem 279:37219 CrossRefGoogle Scholar
  38. 38.
    di Meglio P, Ianaro A, Ghosh S (2005) Arthritis Rheum 52:951 CrossRefGoogle Scholar
  39. 39.
    Jahnke W, Widmer H (2004) Cell Mol Life Sci 61:580 CrossRefGoogle Scholar
  40. 40.
    LeMaster DM (1994) Prog NMR Spectrosc 26:371 CrossRefGoogle Scholar
  41. 41.
    Yang D, Gardner KH, Kay LE (1998) J Biomol NMR 11:213 CrossRefGoogle Scholar
  42. 42.
    Ravindranathan S, Mallet J-M, Sinay P, Bodenhausen G (2003) J Magn Res 163:199207 CrossRefGoogle Scholar
  43. 43.
    Yang D, Kay LE (1998) J Am Chem Soc 120:9880 CrossRefGoogle Scholar
  44. 44.
    Pelupessy P, Chiarparin E, Ghose R, Bodenhausen G (1999) J Biomol NMR 14:277 CrossRefGoogle Scholar
  45. 45.
    Kloiber K, Konrad R (2000) J Biomol NMR 17:265 CrossRefGoogle Scholar
  46. 46.
    Chiarparin E, Pelupessy P, Ghose R, Bodenhausen G (2000) J Am Chem Soc 122:1758 CrossRefGoogle Scholar
  47. 47.
    Crowley P, Ubbink M, Otting G (2000) J Am Chem Soc 122:2968 CrossRefGoogle Scholar
  48. 48.
    Havel TF (1991) Prog Biophys Mol Biol 56:43 CrossRefGoogle Scholar
  49. 49.
    Bohm H-J, Schneider G (2003) Protein-Ligand Interactions From Molecular Recognition to Drug Design. Methods Princ Med Chem, vol 19. Wiley-VCH, Weinheim, Germany CrossRefGoogle Scholar
  50. 50.
    Alvarez J, Shoichet B (2005) Virtual Screening in Drug Discovery. CRC-Press, Boca Raton, FL CrossRefGoogle Scholar
  51. 51.
    Otting G, Wüthrich K (1990) Quart Rev Biophys 23:39 CrossRefGoogle Scholar
  52. 52.
    McCoy MA, Wyss DF (2000) J Biomol NMR 18:189 CrossRefGoogle Scholar
  53. 53.
    Mayer M, Meyer B (2001) J Am Chem Soc 123:6108 CrossRefGoogle Scholar
  54. 54.
    Koenig BW (2007) Top Curr Chem 272:187 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Marcel J. J. Blommers
    • 1
    Email author
  • Andre Strauss
    • 1
  • Martin Geiser
    • 1
  • Paul Ramage
    • 1
  • Helmut Sparrer
    • 1
  • Wolfgang Jahnke
    • 1
  1. 1.Novartis Institutes for BioMedical Research, Discovery TechnologiesBaselSwitzerland

Personalised recommendations