Perspectives in Drug Discovery and Design

, Volume 3, Issue 1, pp 168–195 | Cite as

Backward binding and other structural surprises

  • Edgar F. Meyer
  • Istvan Botos
  • Leonardo Scapozza
  • Dachuan Zhang


From simple to highly complex molecules, examples are cited of ‘backward’ or retro-binding. In some cases, symmetry dictates the directions observed and in cases not treated here, statistical disorder reveals averaged forward/backward binding. In most of the cases found, both the receptor and the ligand(s) are asymmetric, so local interactions dictate the preferred binding mode. A general rationale is presented to explain some of these observations and a hypothesis derived from this review can be tested experimentally.


Polymer General Rationale Binding Mode Local Interaction Complex Molecule 


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  1. 1.
    Fischer, E., Ber. Deutschen Chem. Gesellsch., 27 (1894) 2984.Google Scholar
  2. 2.
    Meyer, E.F., Pharm. Acta Helv., 69 (1995) 177; ETH, Zürich, April 15–16, 1994.Google Scholar
  3. 3.
    Saraste, M. and Musacchio, A., Nature Struct. Biol., 1 (1994) 835.Google Scholar
  4. 4.
    Mattos, C. and Ringe, D., In Kubinyi, H. (Ed.) 3D QSAR in Drug Design: Theory, Methods and Applications, ESCOM, Leiden, 1993, pp. 226–254.Google Scholar
  5. 5.
    Huber, R., Kukla, D., Bode, W., Schwager, P., Bartels, K., Deisenhofer, J. and Steigemann, W., J. Mol. Biol., 89 (1974) 73.Google Scholar
  6. 6.
    Lybrand, T.P. and McCammon, J.A., J. Comput.-Aided Mol. Design, 2 (1988) 259.Google Scholar
  7. 7.
    Chow, M.M., Meyer, E., Bode, W., Kam, C.-H., Radhakrishnan, R., Vijayalakshmi, J. and Powers, J.C., J. Am. Chem. Soc., 112 (1990) 7783.Google Scholar
  8. 8.
    Bode, W., Meyer, E. and Powers, J.C., Biochemistry, 28 (1989) 1951.Google Scholar
  9. 9.
    Heilbronner, E. and Dunitz, J.D., Reflections on Symmetry in Chemistry... and Elsewhere, Verlag Helvetica Chimica Acta, Basel/VCH Verlagsgesellschaft, Weinheim/VCH Publishers, New York, 1993.Google Scholar
  10. 10.
    Luisi, B.F., Xu, W.X., Otwinowski, Z., Freeman, L.P., Yamamoto, K.R. and Sigler, P.B., Nature, 352 (1991) 497.Google Scholar
  11. 11.
    Schwabe, J.W.R., Chapman, L., Finch, J.T. and Rhodes, D., Cell, 75 (1993) 567.Google Scholar
  12. 12.
    Beamer, L.J. and Pabo, C.O., J. Mol. Biol., 227 (1992) 177.Google Scholar
  13. 13.
    Rose, R.B., Rosé, J.R., Salto, R., Craik, C.S. and Stroud, R.M., Biochemistry, 32 (1993) 12498.Google Scholar
  14. 14.
    Appelt, K., Perspect. Drug Discov. Design, 1 (1993) 23.Google Scholar
  15. 15.
    Wlodawer, A. and Erickson, J.W., Annu. Rev. Biochem., 62 (1993) 543.Google Scholar
  16. 16.
    Reich, S.H., Melnick, M., Davies II, J.F., Appelt, K., Lewis, K.K., Fuhry, M.A., Pino, M., Trippe, A.J., Nguyen, D., Dawson, H., Wu, B., Musick, L., Kosa, M., Kahil, D., Webber, S., Gehlhaar, D.K., Andrada, D. and Shetty, B., Proc. Natl. Acad. Sci. USA, 92 (1995) 3298.Google Scholar
  17. 17.
    Milton, R.C. deL., Milton, S.C.F. and Kent, S.B.H., Science, 256 (1992) 1445.Google Scholar
  18. 18.
    Rutenber, E., Fauman, E.B., Keenan, R.J., Fong, S., Furth, P.S., Ortiz de Montellano, P.R., Meng, E., Kuntz, I.D., DeCamp, D.L., Salto, R., Rosé, J.R., Craik, C.S. and Stroud, R.M., J. Biol. Chem., 268 (1993) 15343.Google Scholar
  19. 19.
    Minor Jr., D.L. and Kim, P.S., Nature, 371 (1994) 264.Google Scholar
  20. 20.
    Zhang, D., Botos, I., Gomis-Rüth, F.X., Doll, R., Blood, C., Njoroge, F.G., Fox, J., Bode, W. and Meyer, E.F., Proc. Natl. Acad. Sci. USA, 91 (1994) 8447.Google Scholar
  21. 21.
    Schechter, I. and Berger, A., Biochem. Biophys. Res. Commun., 27 (1967) 157.Google Scholar
  22. 22.
    Hughes, D.L., Sieker, L.C., Bieth, J. and Dimicoli, J.L., J. Mol. Biol., 162 (1982) 645.Google Scholar
  23. 23.
    Meyer, E.F., Radhakrishnan, R., Cole, G.M. and Presta, L.G., J. Mol. Biol., 189 (1986) 533.Google Scholar
  24. 24.
    Iwanowicz, E.J., Lau, W.F., Lin, J., Roberts, D.G.M. and Seiler, S.M., J. Med. Chem., 37 (1994) 2122.Google Scholar
  25. 25.
    Tabernero, L., Chang, C.Y.Y., Ohringer, S.L., Lau, W.F., Iwanowicz, E.J., Han, W., Wang, T.C., Seiler, S.M., Roberts, D.G.M. and Sack, J.S., J. Mol. Biol., 246 (1995) 14.Google Scholar
  26. 26.
    Grütter, M.G., Priestle, J.P., Rahuel, J., Grossenbacher, H., Bode, W., Hofsteenge, J. and Stone, S.R., EMBO J., 9 (1990) 2361.Google Scholar
  27. 27.
    Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S.R. and Hofsteenge, J., EMBO J., 8 (1989) 3467.Google Scholar
  28. 28.
    Woessner Jr., J.F., FASEB J., 5 (1991) 2145.Google Scholar
  29. 29.
    Lim, W.A., Fox, R.O. and Richards, F.M., Protein Sci., 3 (1994) 1261.Google Scholar
  30. 30.
    Lim, W.A. and Richards, F.M., Nature Struct. Biol., 1 (1994) 221.Google Scholar
  31. 31.
    Terasawa, H., Kohda, D., Hatanaka, H., Tsuchiya, S., Ogura, K., Nagata, K., Ishii, S., Mandiyan, V., Ullrich, A., Schlessinger, J. and Inagaki, F., Nature Struct. Biol., 1 (1994) 891.Google Scholar
  32. 32.
    Goudreau, N., Cornille, F., Duchesne, M., Parker, F., Tocque, B., Garbay, C. and Roques, B.P., Nature Struct. Biol., 1 (1994) 898.Google Scholar
  33. 33.
    Lim, W.A., Richards, F.M. and Fox, R.O., Nature, 372 (1994) 375.Google Scholar
  34. 34.
    Rozakis-Adcock, M., Fernley, R., Wade, J., Pawson, T. and Bowtell, D., Nature, 363 (1993) 83.Google Scholar
  35. 35.
    Musacchio, A., Saraste, M. and Willimans, M., Nature Struct. Biol., 1 (1994) 546.Google Scholar
  36. 36.
    Ren, R., Mayer, B.J., Cicchetti, P. and Baltimore, D., Science, 259 (1993) 1157.Google Scholar
  37. 37.
    Kim, K.H., Willingmann, P., Gong, Z.X., Kremer, M.J., Chapman, M.S., Minor, I., Oliveira, M.A., Rossmann, M.G., Andries, K., Diana, G.D., Dutko, F.J., McKinlay, M.A. and Pevear, D.C., J. Mol. Biol., 230 (1993) 206.Google Scholar
  38. 38.
    Badger, J., Minor, I., Kremer, M.J., Oliveira, M.A., Smith, T.J., Griffith, J.P., Guerin, D.M.A., Krishnaswamy, S., Luo, M., Rossmann, M.G., McKinlay, M.A., Diana, G.D., Dutko, F.J., Fancher, M., Rueckert, R.R. and Heinz, B.A., Proc. Natl. Acad. Sci. USA, 85 (1988) 3304.Google Scholar
  39. 39.
    Smith, T.J., Kremer, M.J., Luo, M., Vriend, G., Arnold, E., Kamer, G., Rossmann, M.G., McKinlay, M.A., Diana, G.D. and Otto, M.J., Science, 233 (1986) 1286.Google Scholar
  40. 40.
    Chapman, M.S., Minor, I. and Rossmann, M.G., J. Mol. Biol., 217 (1991) 455.Google Scholar
  41. 41.
    Gatti, D.L., Palfey, B.A., Lah, M.S., Entsch, B., Massey, V., Ballou, D.P. and Ludwig, M.L., Science, 266 (1994) 110.Google Scholar
  42. 42.
    Bolin, J.T., Filman, D.J., Matthews, D.A., Hamlin, R.C. and Kraut, J., J. Biol. Chem., 257 (1982) 13650.Google Scholar
  43. 43.
    Oefner, C., D'Arcy, A. and Winkler, F.K., Eur. J. Biochem., 174 (1988) 377.Google Scholar
  44. 44.
    Bystroff, C., Oatley, S.J. and Kraut, J., Biochemistry, 29 (1990) 3263.Google Scholar
  45. 45.
    Davies, J.F., Delcamp, T.J., Prendergast, N.J., Ashford, V.A., Freisheim, J.H. and Kraut, J., Biochemistry, 29 (1990) 9467.Google Scholar
  46. 46.
    Aguilar, C.F., Thomas, P.J., Moss, D.S., Mills, A. and Palmer, R.A., Biochim. Biophys. Acta, 1118 (1991) 6.Google Scholar
  47. 47.
    Erion, M.D., Niwas, S., Rose, J.D., Ananthan, S., Allen, M., Secrist III, J.A., Babu, Y.S., Bugg, C.E., Guida, W.G., Ealick, S.E. and Montgomery, J.A., J. Med. Chem., 36 (1993) 3771.Google Scholar
  48. 48.
    Carrell, H.L., Hoier, H. and Glusker, J.P., Acta Crystallogr., D50 (1994) 113.Google Scholar
  49. 49.
    Weber, P.C., Pantoliano, M.W., Simons, D.M. and Salemme, F.R., J. Am. Chem. Soc., 116 (1994) 2717.Google Scholar
  50. 50.
    Klimasauskas, S., Kumar, S., Roberts, R.J. and Cheng, X., Cell, 76 (1994) 357.Google Scholar
  51. 51.
    Winkler, F.K., Structure, 2 (1994) 79.Google Scholar
  52. 52.
    Rognan, D., Scapozza, L., Folkers, G. and Daser, A., Biochemistry, 33 (1994) 11476.Google Scholar
  53. 53.
    Saito, Y., Peterson, P.A. and Matsamura, M., J. Biol. Chem., 268 (1993) 21309.Google Scholar
  54. 54.
    Dutler, H. and Bizzozero, S.A., Acc. Chem. Res., 22 (1989) 322.Google Scholar
  55. 55.
    Meyer, E., Clore, G.M., Gronenborn, A.M. and Hansen, H.A.S., Biochemistry, 27 (1988) 725.Google Scholar
  56. 56.
    Pisabarro, M.T., Ortiz, A.R., Viguera, A.R., Gago, F. and Serrano, L., Protein Eng., 7 (1994) 1455.Google Scholar
  57. 57a.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.Google Scholar
  58. 57b.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., Eur. J. Biochem., 80 (1977) 319.Google Scholar
  59. 57c.
    Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., Arch. Biochem. Biophys., 185 (1978) 584.Google Scholar
  60. 58.
    Meyer, E., Protein Sci., 1 (1992) 1543.Google Scholar
  61. 59.
    Nicholls, A., Sharp, K. and Honig, B., Protein Struct. Funct. Genet., 4 (1991) 281.Google Scholar
  62. 60.
    Niedwzwiecki, L., Teahan, J., Harrison, R.K. and Stein, R.L., Biochemistry, 31 (1992) 12618.Google Scholar
  63. 61.
    Netzel-Arnett, S., Mallya, S.K., Nagase, K., Birkedal-Hansen, H. and Van Wart, H.E., Anal. Biochem., 195 (1991) 86.Google Scholar
  64. 62.
    Knight, C.G., Willenbrock, F. and Murphy, G., FEBS Lett., 296 (1992) 263.Google Scholar
  65. 63.
    Weiner, S.J., Kollman, P.A., Case, D.A., Singh, U.C., Ghio, C., Alagona, G., Profeta Jr., S. and Weiner, P.A., J. Am. Chem. Soc., 106 (1984) 765.Google Scholar
  66. 64.
    Gilson, M.K., Sharp, K.A. and Honig, B., J. Comput. Chem., 9 (1987) 327.Google Scholar
  67. 65.
    Connolly, M.L., J. Appl. Crystallogr., 16 (1983) 548.Google Scholar

Copyright information

© ESCOM Science Publishers B.V 1995

Authors and Affiliations

  • Edgar F. Meyer
    • 1
  • Istvan Botos
    • 1
  • Leonardo Scapozza
    • 1
  • Dachuan Zhang
    • 1
  1. 1.Biographics Laboratory, Department of Biochemistry and BiophysicsTexas A&M UniversityCollege StationU.S.A.

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