Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1984 Mar 15;218(3):677–689. doi: 10.1042/bj2180677

X-ray diffraction studies of enkephalins. Crystal structure of [(4'-bromo) Phe4,Leu5]enkephalin.

T Ishida, M Kenmotsu, Y Mino, M Inoue, T Fujiwara, K Tomita, T Kimura, S Sakakibara
PMCID: PMC1153395  PMID: 6721829

Abstract

In order to investigate the structure-activity relationship of [Leu5]- and [Met5]enkephalins, [(4'-bromo)Phe4, Leu5]-, [(4'-bromo)Phe4, Met5]- and [Met5] enkephalins were synthesized and crystallized. The crystal structure of [(4'-bromo) Phe4, Leu5]- enkephalin was determined by X-ray diffraction method using the heavy atom method and refined to R = 0.092 by the least-squares method. The molecule in this crystal took essentially the same type I' beta-turn conformation found in [Leu5]enkephalin [Smith & Griffin (1978) Science 199, 1214-1216). On the other hand, the preliminary three-dimensional Patterson analyses showed that the most probable conformations of [(4'-bromo)Phe4,Met5]- and [Met5]enkephalins are both the dimeric extended forms. Based on these insights, the biologically active conformation of enkephalin was discussed in relation to the mu- and delta-receptors.

Full text

PDF
677

Selected References

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

  1. Balodis Y. Y., Nikiforovich G. V., Grinsteine I. V., Vegner R. E., Chipens G. I. Enkephalin: structure--function relationships. FEBS Lett. 1978 Feb 15;86(2):239–242. doi: 10.1016/0014-5793(78)80570-5. [DOI] [PubMed] [Google Scholar]
  2. Bhat T. N., Sasisekharan V., Vijayan M. An analysis of side-chain conformation in proteins. Int J Pept Protein Res. 1979 Feb;13(2):170–184. doi: 10.1111/j.1399-3011.1979.tb01866.x. [DOI] [PubMed] [Google Scholar]
  3. Bleich H. E., Day A. R., Freer R. J., Glasel J. A. 360 MHz proton NMR spectra of active and inactive derivatives of methionine-enkephalin. Assignments, derived parameters, conformational implications. Biochem Biophys Res Commun. 1977 Jan 24;74(2):592–598. doi: 10.1016/0006-291x(77)90344-8. [DOI] [PubMed] [Google Scholar]
  4. Bradbury A. F., Smyth D. G., Snell C. R. Biosynthetic origin and receptor conformation of methionine enkephalin. Nature. 1976 Mar 11;260(5547):165–166. doi: 10.1038/260165a0. [DOI] [PubMed] [Google Scholar]
  5. Chang J. K., Fong B. T., Pert A., Pert C. B. Opiate receptor affinities and behavioral effects of enkephalin: structure-activity relationship of ten synthetic peptide analogues. Life Sci. 1976 Jun 15;18(12):1473–1481. doi: 10.1016/0024-3205(76)90366-0. [DOI] [PubMed] [Google Scholar]
  6. Chang K. J., Cuatrecasas P. Multiple opiate receptors. Enkephalins and morphine bind to receptors of different specificity. J Biol Chem. 1979 Apr 25;254(8):2610–2618. [PubMed] [Google Scholar]
  7. Chang K. J., Hazum E., Cuatrecasas P. Possible role of distinct morphine and enkephalin receptors in mediating actins of benzomorphan drugs (putative kappa and sigma agonists). Proc Natl Acad Sci U S A. 1980 Aug;77(8):4469–4473. doi: 10.1073/pnas.77.8.4469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Childers S. R., Creese I., Snowman A. M., Synder S. H. Opiate receptor binding affected differentially by opiates and opioid peptides. Eur J Pharmacol. 1979 Apr 1;55(1):11–18. doi: 10.1016/0014-2999(79)90142-0. [DOI] [PubMed] [Google Scholar]
  9. Clarke F. H., Jaggi H., Lovell R. A. Conformation of 2,9-dimethyl-3'-hydroxy-5-phenyl-6,7-genzomorphan and its relation to other analgetics and enkephalin. J Med Chem. 1978 Jul;21(7):600–606. doi: 10.1021/jm00205a003. [DOI] [PubMed] [Google Scholar]
  10. De Coen J. L., Humblet C., Koch M. H. Theoretical conformational analysis of Met-enkephalin. FEBS Lett. 1977 Jan 15;73(1):38–42. [PubMed] [Google Scholar]
  11. DiMaio J., Nguyen T. M., Lemieux C., Schiller P. W. Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogues: effect of conformational constraints on opiate receptor selectivity. J Med Chem. 1982 Dec;25(12):1432–1438. doi: 10.1021/jm00354a008. [DOI] [PubMed] [Google Scholar]
  12. Feinberg A. P., Creese I., Snyder S. H. The opiate receptor: a model explaining structure-activity relationships of opiate agonists and antagonists. Proc Natl Acad Sci U S A. 1976 Nov;73(11):4215–4219. doi: 10.1073/pnas.73.11.4215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fischman A. J., Riemen M. W., Cowburn D. Averaging of phi2 and phi3 in [5-leucyl]-enkephalin: NMR study of two isotopic isomers. FEBS Lett. 1978 Oct 15;94(2):236–240. doi: 10.1016/0014-5793(78)80945-4. [DOI] [PubMed] [Google Scholar]
  14. Garbay-Jaureguiberry C., Baudet J., Florentin D., Roques B. P. Conformational analysis of linear peptides by 15N NMR spectroscopy using the enkephalin-related fragment Tyr-Gly-Gly-Phe as a model compound. FEBS Lett. 1980 Jun 30;115(2):315–318. doi: 10.1016/0014-5793(80)81196-3. [DOI] [PubMed] [Google Scholar]
  15. Garbay-Jaureguiberry C., Roques B. P., Oberlin R. 1H and 13C NMR studies of conformational behaviour of Leu-enkephalin. FEBS Lett. 1977 Apr 1;76(1):93–98. doi: 10.1016/0014-5793(77)80128-2. [DOI] [PubMed] [Google Scholar]
  16. Gorin F. A., Balasubramanian T. M., Barry C. D., Marshall G. R. Elucidation of the receptor-bound conformation of the enkephalins. J Supramol Struct. 1978;9(1):27–39. doi: 10.1002/jss.400090104. [DOI] [PubMed] [Google Scholar]
  17. Gorin F. A., Marshall G. R. Proposal for the biologically active conformation of opiates and enkephalin. Proc Natl Acad Sci U S A. 1977 Nov;74(11):5179–5183. doi: 10.1073/pnas.74.11.5179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Han S. L., Stimson E. R., Maxfield F. R., Scheraga H. A. Conformational study of [Leu5]-enkephalin by laser Raman spectroscopy. Int J Pept Protein Res. 1980 Sep;16(3):173–181. [PubMed] [Google Scholar]
  19. Higashijima T., Kobayashi J., Nagai U., Miyazawa T. Nuclear-magnetic-resonance study on Met-enkephalin and Met-enkephalinamide. Molecular association and conformation. Eur J Biochem. 1979 Jun;97(1):43–57. doi: 10.1111/j.1432-1033.1979.tb13084.x. [DOI] [PubMed] [Google Scholar]
  20. Horn A. S., Rodgers J. R. Structural and conformational relationships between the enkephalins and the opiates. Nature. 1976 Apr 29;260(5554):795–797. doi: 10.1038/260795a0. [DOI] [PubMed] [Google Scholar]
  21. Horn A. S., Rodgers J. R. The enkephalins and opiates: structure-activity relations. J Pharm Pharmacol. 1977 May;29(5):257–265. doi: 10.1111/j.2042-7158.1977.tb11308.x. [DOI] [PubMed] [Google Scholar]
  22. Hughes J., Smith T. W., Kosterlitz H. W., Fothergill L. A., Morgan B. A., Morris H. R. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature. 1975 Dec 18;258(5536):577–580. doi: 10.1038/258577a0. [DOI] [PubMed] [Google Scholar]
  23. Hughes J., Smith T., Morgan B., Fothergill L. Purification and properties of enkephalin - the possible endogenous ligand for the morphine receptor. Life Sci. 1975 Jun 15;16(12):1753–1758. doi: 10.1016/0024-3205(75)90268-4. [DOI] [PubMed] [Google Scholar]
  24. Isogai Y., Némethy G., Scheraga H. A. Enkephalin: conformational analysis by means of empirical energy calculations. Proc Natl Acad Sci U S A. 1977 Feb;74(2):414–418. doi: 10.1073/pnas.74.2.414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jones C. R., Garsky V., Gibbons W. Molecular conformations of Met-enkephalin: comparison of the zwitterionic and cationic forms. Biochem Biophys Res Commun. 1977 Jun 6;76(3):619–625. doi: 10.1016/0006-291x(77)91546-7. [DOI] [PubMed] [Google Scholar]
  26. Khaled M. A., Long M. M., Thompson W. D., Bradley R. J., Brown G. B., Urry D. W. Conformational states of enkephalins in solution. Biochem Biophys Res Commun. 1976 May 23;76(2):224–231. doi: 10.1016/0006-291x(77)90715-x. [DOI] [PubMed] [Google Scholar]
  27. Kobayashi J., Higashijima T., Nagai U., Miyazawa T. Nuclear magnetic resonance study of side-chain conformation of tyrosyl residue in [Met5]-enkephalin. Solvent and temperature dependence. Biochim Biophys Acta. 1980 Feb 27;621(2):190–203. doi: 10.1016/0005-2795(80)90171-3. [DOI] [PubMed] [Google Scholar]
  28. Lemaire S., Bérubé A., Derome G., Lemaire I., Magnan J., Regoli D., St Pierre S. Synthesis and biological activity of beta-endorphin and analogues. Additional evidence for multiple opiate receptors. J Med Chem. 1978 Dec;21(12):1232–1235. doi: 10.1021/jm00210a012. [DOI] [PubMed] [Google Scholar]
  29. Ling N., Guillemin R. Morphinomimetic activity of synthetic fragments of beta-lipotropin and analogs. Proc Natl Acad Sci U S A. 1976 Sep;73(9):3308–3310. doi: 10.1073/pnas.73.9.3308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Loew G. H., Burt S. K. Energy conformation study of Met-enkephalin and its D-Ala2 analogue and their resemblance to rigid opiates. Proc Natl Acad Sci U S A. 1978 Jan;75(1):7–11. doi: 10.1073/pnas.75.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lord J. A., Waterfield A. A., Hughes J., Kosterlitz H. W. Endogenous opioid peptides: multiple agonists and receptors. Nature. 1977 Jun 9;267(5611):495–499. doi: 10.1038/267495a0. [DOI] [PubMed] [Google Scholar]
  32. Maigret B., Premilat S. Clustering analysis of enkephalin conformations. Biochem Biophys Res Commun. 1982 Feb 11;104(3):971–976. doi: 10.1016/0006-291x(82)91344-4. [DOI] [PubMed] [Google Scholar]
  33. Manavalan P., Momany F. A. Conformational energy calculations on enkephalins and enkephalin analogs. Classification of conformations to different configurational types. Int J Pept Protein Res. 1981 Sep;18(3):256–275. doi: 10.1111/j.1399-3011.1981.tb02980.x. [DOI] [PubMed] [Google Scholar]
  34. Marsh R. E., Donohue J. Crystal structure studies of amino acids and peptides. Adv Protein Chem. 1967;22:235–256. doi: 10.1016/s0065-3233(08)60042-x. [DOI] [PubMed] [Google Scholar]
  35. Martin W. R., Eades C. G., Thompson J. A., Huppler R. E., Gilbert P. E. The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976 Jun;197(3):517–532. [PubMed] [Google Scholar]
  36. Momany F. A. Conformational analysis of methionine-enkephalin and some analogs. Biochem Biophys Res Commun. 1977 Apr 25;75(4):1098–1103. doi: 10.1016/0006-291x(77)91495-4. [DOI] [PubMed] [Google Scholar]
  37. Morgan B. A., Smith C. F., Waterfield A. A., Hughes J., Kosterlitz H. W. Structure-activity relationships of methionine-enkephalin. J Pharm Pharmacol. 1976 Aug;28(8):660–661. doi: 10.1111/j.2042-7158.1976.tb02827.x. [DOI] [PubMed] [Google Scholar]
  38. Pert C. B., Pert A., Chang J. K., Fong B. T. (D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic. Science. 1976 Oct 15;194(4262):330–332. doi: 10.1126/science.968485. [DOI] [PubMed] [Google Scholar]
  39. Portoghese P. S. A new concept on the mode of interaction of narcotic analgesics with receptors. J Med Chem. 1965 Sep;8(5):609–616. doi: 10.1021/jm00329a013. [DOI] [PubMed] [Google Scholar]
  40. Roemer D., Buescher H. H., Hill R. C., Pless J., Bauer W., Cardinaux F., Closse A., Hauser D., Huguenin R. A synthetic enkephalin analogue with prolonged parenteral and oral analgesic activity. Nature. 1977 Aug 11;268(5620):547–549. doi: 10.1038/268547a0. [DOI] [PubMed] [Google Scholar]
  41. Roques B. P., Garbay-Jaureguiberry C., Oberlin R., Anteunis M., Lala A. K. Conformation of Met5-enkephalin determined by high field PMR spectroscopy. Nature. 1976 Aug 26;262(5571):778–779. doi: 10.1038/262778a0. [DOI] [PubMed] [Google Scholar]
  42. Sasisekharan V., Ponnuswamy P. K. Studies on the conformation of amino acids. X. Conformations of norvalyl, leucyl and aromatic side groups in a dipeptide unit. Biopolymers. 1971;10(3):583–592. doi: 10.1002/bip.360100312. [DOI] [PubMed] [Google Scholar]
  43. Simantov R., Snyder H. Isolation and structure identification of a morphine-like peptide "enkephalin" in bovine brain. Life Sci. 1976 Apr 15;18(8):781–787. doi: 10.1016/0024-3205(76)90002-3. [DOI] [PubMed] [Google Scholar]
  44. Smith D., Griffin J. F. Conformation of [Leu5]enkephalin from X-ray diffraction: features important for recognition at opiate receptor. Science. 1978 Mar 17;199(4334):1214–1216. doi: 10.1126/science.204006. [DOI] [PubMed] [Google Scholar]
  45. Stimson E. R., Meinwald Y. C., Scheraga H. A. Solution conformation of enkephalin. A nuclear magnetic resonance study of 13C-enriched carbonyl carbons in [Leu5]-enkephalin. Biochemistry. 1979 May 1;18(9):1661–1671. doi: 10.1021/bi00576a005. [DOI] [PubMed] [Google Scholar]
  46. Sudha T. S., Balaram P. Conformational flexibility in enkephalins: solvent dependent transitions in peptides with Gly-Gly segments detected by circular dichroism. FEBS Lett. 1981 Nov 2;134(1):32–36. doi: 10.1016/0014-5793(81)80544-3. [DOI] [PubMed] [Google Scholar]
  47. Terenius L., Wahlström A., Lindeberg G., Karlsson S., Ragnarsson U. Opiate receptor affinity of peptides related to Leu-enkephalin. Biochem Biophys Res Commun. 1976 Jul 12;71(1):175–179. doi: 10.1016/0006-291x(76)90265-5. [DOI] [PubMed] [Google Scholar]
  48. Zetta L., Cabassi F. 270-MHz 1H nuclear-magnetic-resonance study of met-enkephalin in solvent mixtures. Conformational transition from dimethylsulphoxide to water. Eur J Biochem. 1982 Feb;122(1):215–222. doi: 10.1111/j.1432-1033.1982.tb05869.x. [DOI] [PubMed] [Google Scholar]

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

RESOURCES