Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1996 Oct 1;319(Pt 1):1–8. doi: 10.1042/bj3190001

Cation-pi bonding and amino-aromatic interactions in the biomolecular recognition of substituted ammonium ligands.

N S Scrutton 1, A R Raine 1
PMCID: PMC1217726  PMID: 8870640

Abstract

Cation-pi bonds and amino-aromatic interactions are known to be important contributors to protein architecture and stability, and their role in ligand-protein interactions has also been reported. Many biologically active amines contain substituted ammonium moieties, and cation-pi bonding and amino-aromatic interactions often enable these molecules to associate with proteins. The role of organic cation-pi bonding and amino-aromatic interactions in the recognition of small-molecule amines and peptides by proteins is an important topic for those involved in structure-based drug design, and although the number of structures determined for proteins displaying these interactions is small, general features are beginning to emerge. This review explores the role of cation-pi bonding and amino-aromatic interactions in the biological molecular recognition of amine ligands. Perspectives on the design of ammonium-ligand-binding sites are also discussed.

Full Text

The Full Text of this article is available as a PDF (485.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bailey S., Smith K., Fairlamb A. H., Hunter W. N. Substrate interactions between trypanothione reductase and N1-glutathionylspermidine disulphide at 0.28-nm resolution. Eur J Biochem. 1993 Apr 1;213(1):67–75. doi: 10.1111/j.1432-1033.1993.tb17734.x. [DOI] [PubMed] [Google Scholar]
  2. Bellamy H. D., Lim L. W., Mathews F. S., Dunham W. R. Studies of crystalline trimethylamine dehydrogenase in three oxidation states and in the presence of substrate and inhibitor. J Biol Chem. 1989 Jul 15;264(20):11887–11892. [PubMed] [Google Scholar]
  3. Boyd G., Mathews F. S., Packman L. C., Scrutton N. S. Trimethylamine dehydrogenase of bacterium W3A1. Molecular cloning, sequence determination and over-expression of the gene. FEBS Lett. 1992 Aug 24;308(3):271–276. doi: 10.1016/0014-5793(92)81291-s. [DOI] [PubMed] [Google Scholar]
  4. Bradley M., Bücheler U. S., Walsh C. T. Redox enzyme engineering: conversion of human glutathione reductase into a trypanothione reductase. Biochemistry. 1991 Jun 25;30(25):6124–6127. doi: 10.1021/bi00239a006. [DOI] [PubMed] [Google Scholar]
  5. Burley S. K., Petsko G. A. Amino-aromatic interactions in proteins. FEBS Lett. 1986 Jul 28;203(2):139–143. doi: 10.1016/0014-5793(86)80730-x. [DOI] [PubMed] [Google Scholar]
  6. Cantley L. C., Auger K. R., Carpenter C., Duckworth B., Graziani A., Kapeller R., Soltoff S. Oncogenes and signal transduction. Cell. 1991 Jan 25;64(2):281–302. doi: 10.1016/0092-8674(91)90639-g. [DOI] [PubMed] [Google Scholar]
  7. Chen L., Mathews F. S., Davidson V. L., Huizinga E. G., Vellieux F. M., Hol W. G. Three-dimensional structure of the quinoprotein methylamine dehydrogenase from Paracoccus denitrificans determined by molecular replacement at 2.8 A resolution. Proteins. 1992 Oct;14(2):288–299. doi: 10.1002/prot.340140214. [DOI] [PubMed] [Google Scholar]
  8. Chistoserdov A. Y., Boyd J., Mathews F. S., Lidstrom M. E. The genetic organization of the mau gene cluster of the facultative autotroph Paracoccus denitrificans. Biochem Biophys Res Commun. 1992 May 15;184(3):1181–1189. doi: 10.1016/s0006-291x(05)80007-5. [DOI] [PubMed] [Google Scholar]
  9. Davies D. R., Metzger H. Structural basis of antibody function. Annu Rev Immunol. 1983;1:87–117. doi: 10.1146/annurev.iy.01.040183.000511. [DOI] [PubMed] [Google Scholar]
  10. Dennis M., Giraudat J., Kotzyba-Hibert F., Goeldner M., Hirth C., Chang J. Y., Lazure C., Chrétien M., Changeux J. P. Amino acids of the Torpedo marmorata acetylcholine receptor alpha subunit labeled by a photoaffinity ligand for the acetylcholine binding site. Biochemistry. 1988 Apr 5;27(7):2346–2357. doi: 10.1021/bi00407a016. [DOI] [PubMed] [Google Scholar]
  11. Dougherty D. A. Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science. 1996 Jan 12;271(5246):163–168. doi: 10.1126/science.271.5246.163. [DOI] [PubMed] [Google Scholar]
  12. Eck M. J., Shoelson S. E., Harrison S. C. Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck. Nature. 1993 Mar 4;362(6415):87–91. doi: 10.1038/362087a0. [DOI] [PubMed] [Google Scholar]
  13. Fairlamb A. H. Novel biochemical pathways in parasitic protozoa. Parasitology. 1989;99 (Suppl):S93–112. doi: 10.1017/s003118200008344x. [DOI] [PubMed] [Google Scholar]
  14. Flocco M. M., Mowbray S. L. Planar stacking interactions of arginine and aromatic side-chains in proteins. J Mol Biol. 1994 Jan 14;235(2):709–717. doi: 10.1006/jmbi.1994.1022. [DOI] [PubMed] [Google Scholar]
  15. Galzi J. L., Revah F., Black D., Goeldner M., Hirth C., Changeux J. P. Identification of a novel amino acid alpha-tyrosine 93 within the cholinergic ligands-binding sites of the acetylcholine receptor by photoaffinity labeling. Additional evidence for a three-loop model of the cholinergic ligands-binding sites. J Biol Chem. 1990 Jun 25;265(18):10430–10437. [PubMed] [Google Scholar]
  16. Gao J., Chou L. W., Auerbach A. The nature of cation-pi binding: interactions between tetramethylammonium ion and benzene in aqueous solution. Biophys J. 1993 Jul;65(1):43–47. doi: 10.1016/S0006-3495(93)81031-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Harel M., Schalk I., Ehret-Sabatier L., Bouet F., Goeldner M., Hirth C., Axelsen P. H., Silman I., Sussman J. L. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9031–9035. doi: 10.1073/pnas.90.19.9031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hatada M. H., Lu X., Laird E. R., Green J., Morgenstern J. P., Lou M., Marr C. S., Phillips T. B., Ram M. K., Theriault K. Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor. Nature. 1995 Sep 7;377(6544):32–38. doi: 10.1038/377032a0. [DOI] [PubMed] [Google Scholar]
  19. Henderson G. B., Murgolo N. J., Kuriyan J., Osapay K., Kominos D., Berry A., Scrutton N. S., Hinchliffe N. W., Perham R. N., Cerami A. Engineering the substrate specificity of glutathione reductase toward that of trypanothione reduction. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8769–8773. doi: 10.1073/pnas.88.19.8769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hogan J. K., Pittol C. A., Jones J. B., Gold M. Improved specificity toward substrates with positively charged side chains by site-directed mutagenesis of the L-lactate dehydrogenase of Bacillus stearothermophilus. Biochemistry. 1995 Apr 4;34(13):4225–4230. doi: 10.1021/bi00013a011. [DOI] [PubMed] [Google Scholar]
  21. Hunter W. N., Bailey S., Habash J., Harrop S. J., Helliwell J. R., Aboagye-Kwarteng T., Smith K., Fairlamb A. H. Active site of trypanothione reductase. A target for rational drug design. J Mol Biol. 1992 Sep 5;227(1):322–333. doi: 10.1016/0022-2836(92)90701-k. [DOI] [PubMed] [Google Scholar]
  22. Karplus P. A., Pai E. F., Schulz G. E. A crystallographic study of the glutathione binding site of glutathione reductase at 0.3-nm resolution. Eur J Biochem. 1989 Jan 2;178(3):693–703. doi: 10.1111/j.1432-1033.1989.tb14500.x. [DOI] [PubMed] [Google Scholar]
  23. Karplus P. A., Schulz G. E. Refined structure of glutathione reductase at 1.54 A resolution. J Mol Biol. 1987 Jun 5;195(3):701–729. doi: 10.1016/0022-2836(87)90191-4. [DOI] [PubMed] [Google Scholar]
  24. Karplus P. A., Schulz G. E. Substrate binding and catalysis by glutathione reductase as derived from refined enzyme: substrate crystal structures at 2 A resolution. J Mol Biol. 1989 Nov 5;210(1):163–180. doi: 10.1016/0022-2836(89)90298-2. [DOI] [PubMed] [Google Scholar]
  25. Kasprzak A. A., Papas E. J., Steenkamp D. J. Identity of the subunits and the stoicheiometry of prosthetic groups in trimethylamine dehydrogenase and dimethylamine dehydrogenase. Biochem J. 1983 Jun 1;211(3):535–541. doi: 10.1042/bj2110535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Koch C. A., Anderson D., Moran M. F., Ellis C., Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991 May 3;252(5006):668–674. doi: 10.1126/science.1708916. [DOI] [PubMed] [Google Scholar]
  27. Levitt M., Perutz M. F. Aromatic rings act as hydrogen bond acceptors. J Mol Biol. 1988 Jun 20;201(4):751–754. doi: 10.1016/0022-2836(88)90471-8. [DOI] [PubMed] [Google Scholar]
  28. Liaw S. H., Kuo I., Eisenberg D. Discovery of the ammonium substrate site on glutamine synthetase, a third cation binding site. Protein Sci. 1995 Nov;4(11):2358–2365. doi: 10.1002/pro.5560041114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lim L. W., Shamala N., Mathews F. S., Steenkamp D. J., Hamlin R., Xuong N. H. Three-dimensional structure of the iron-sulfur flavoprotein trimethylamine dehydrogenase at 2.4-A resolution. J Biol Chem. 1986 Nov 15;261(32):15140–15146. [PubMed] [Google Scholar]
  30. Mitchell J. B., Nandi C. L., McDonald I. K., Thornton J. M., Price S. L. Amino/aromatic interactions in proteins: is the evidence stacked against hydrogen bonding? J Mol Biol. 1994 Jun 3;239(2):315–331. doi: 10.1006/jmbi.1994.1370. [DOI] [PubMed] [Google Scholar]
  31. NACHMANSOHN D., WILSON I. B. The enzymic hydrolysis and synthesis of acetylcholine. Adv Enzymol Relat Subj Biochem. 1951;12:259–339. doi: 10.1002/9780470122570.ch5. [DOI] [PubMed] [Google Scholar]
  32. Narula S. S., Yuan R. W., Adams S. E., Green O. M., Green J., Philips T. B., Zydowsky L. D., Botfield M. C., Hatada M., Laird E. R. Solution structure of the C-terminal SH2 domain of the human tyrosine kinase Syk complexed with a phosphotyrosine pentapeptide. Structure. 1995 Oct 15;3(10):1061–1073. doi: 10.1016/s0969-2126(01)00242-8. [DOI] [PubMed] [Google Scholar]
  33. Ponasik J. A., Strickland C., Faerman C., Savvides S., Karplus P. A., Ganem B. Kukoamine A and other hydrophobic acylpolyamines: potent and selective inhibitors of Crithidia fasciculata trypanothione reductase. Biochem J. 1995 Oct 15;311(Pt 2):371–375. doi: 10.1042/bj3110371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Raine A. R., Yang C. C., Packman L. C., White S. A., Mathews F. S., Scrutton N. S. Protein recognition of ammonium cations using side-chain aromatics: a structural variation for secondary ammonium ligands. Protein Sci. 1995 Dec;4(12):2625–2628. doi: 10.1002/pro.5560041222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rohlfs R. J., Hille R. The reaction of trimethylamine dehydrogenase with diethylmethylamine. J Biol Chem. 1994 Dec 9;269(49):30869–30879. [PubMed] [Google Scholar]
  36. Satow Y., Cohen G. H., Padlan E. A., Davies D. R. Phosphocholine binding immunoglobulin Fab McPC603. An X-ray diffraction study at 2.7 A. J Mol Biol. 1986 Aug 20;190(4):593–604. doi: 10.1016/0022-2836(86)90245-7. [DOI] [PubMed] [Google Scholar]
  37. Scott J. K., Smith G. P. Searching for peptide ligands with an epitope library. Science. 1990 Jul 27;249(4967):386–390. doi: 10.1126/science.1696028. [DOI] [PubMed] [Google Scholar]
  38. Singh J., Thornton J. M. SIRIUS. An automated method for the analysis of the preferred packing arrangements between protein groups. J Mol Biol. 1990 Feb 5;211(3):595–615. doi: 10.1016/0022-2836(90)90268-Q. [DOI] [PubMed] [Google Scholar]
  39. Sullivan F. X., Sobolov S. B., Bradley M., Walsh C. T. Mutational analysis of parasite trypanothione reductase: acquisition of glutathione reductase activity in a triple mutant. Biochemistry. 1991 Mar 19;30(11):2761–2767. doi: 10.1021/bi00225a004. [DOI] [PubMed] [Google Scholar]
  40. Sussman J. L., Harel M., Frolow F., Oefner C., Goldman A., Toker L., Silman I. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science. 1991 Aug 23;253(5022):872–879. doi: 10.1126/science.1678899. [DOI] [PubMed] [Google Scholar]
  41. Tüchsen E., Woodward C. Assignment of asparagine-44 side-chain primary amide 1H NMR resonances and the peptide amide N1H resonance of glycine-37 in basic pancreatic trypsin inhibitor. Biochemistry. 1987 Apr 7;26(7):1918–1925. doi: 10.1021/bi00381a020. [DOI] [PubMed] [Google Scholar]
  42. Vellieux F. M., Huitema F., Groendijk H., Kalk K. H., Jzn J. F., Jongejan J. A., Duine J. A., Petratos K., Drenth J., Hol W. G. Structure of quinoprotein methylamine dehydrogenase at 2.25 A resolution. EMBO J. 1989 Aug;8(8):2171–2178. doi: 10.1002/j.1460-2075.1989.tb08339.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vellieux F. M., Kalk K. H., Drenth J., Hol W. G. Structure determination of quinoprotein methylamine dehydrogenase from Thiobacillus versutus. Acta Crystallogr B. 1990 Dec 1;46(Pt 6):806–823. doi: 10.1107/s010876819000636x. [DOI] [PubMed] [Google Scholar]
  44. Waksman G., Kominos D., Robertson S. C., Pant N., Baltimore D., Birge R. B., Cowburn D., Hanafusa H., Mayer B. J., Overduin M. Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature. 1992 Aug 20;358(6388):646–653. doi: 10.1038/358646a0. [DOI] [PubMed] [Google Scholar]
  45. Waksman G., Shoelson S. E., Pant N., Cowburn D., Kuriyan J. Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms. Cell. 1993 Mar 12;72(5):779–790. doi: 10.1016/0092-8674(93)90405-f. [DOI] [PubMed] [Google Scholar]
  46. Wlodawer A., Walter J., Huber R., Sjölin L. Structure of bovine pancreatic trypsin inhibitor. Results of joint neutron and X-ray refinement of crystal form II. J Mol Biol. 1984 Dec 5;180(2):301–329. doi: 10.1016/s0022-2836(84)80006-6. [DOI] [PubMed] [Google Scholar]
  47. Yang C. C., Packman L. C., Scrutton N. S. The primary structure of Hyphomicrobium X dimethylamine dehydrogenase. Relationship to trimethylamine dehydrogenase and implications for substrate recognition. Eur J Biochem. 1995 Aug 15;232(1):264–271. doi: 10.1111/j.1432-1033.1995.tb20808.x. [DOI] [PubMed] [Google Scholar]
  48. Zhou M. M., Meadows R. P., Logan T. M., Yoon H. S., Wade W. S., Ravichandran K. S., Burakoff S. J., Fesik S. W. Solution structure of the Shc SH2 domain complexed with a tyrosine-phosphorylated peptide from the T-cell receptor. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7784–7788. doi: 10.1073/pnas.92.17.7784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Zvelebil M. J., Panayotou G., Linacre J., Waterfield M. D. Prediction and analysis of SH2 domain-phosphopeptide interactions. Protein Eng. 1995 Jun;8(6):527–533. doi: 10.1093/protein/8.6.527. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES