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The crystal structure of human endothelin

Nature Structural Biology volume 1, pages 311–319 (1994)Cite this article

Abstract

The three–dimensional structure of the vasoactive polypeptide endothelin, the most potent vasocontrictor yet identified, has been determined by X–ray crystallography to 2.18 Å resolution. This intermediate–sized structure was solved by molecular replacement techniques using a fragment of an NMR–derived model for initial phasing of the data. However, comparisons of the final X–ray structure with the many diverse models derived from NMR data indicate some important differences, especially in the carboxy–terminal region of the molecule: the entire carboxy terminal tail (residues 16–21) is helical in the crystal structure, but not in any of the NMR structures. This may be a functionally significant difference as this region is crucial for receptor binding and vasoactivity.

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References

  1. Yanagisawa, M. et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells.. Nature 332, 411–415 (1988).

    Article  CAS  Google Scholar 

  2. Kumagaye, S. et al. Synthesis and disulfide structure determination of porcine endothelin: an endothelium-derived vasoconstricting peptide. Int. J. Peptide Protein Res. 32, 519–526 (1988).

    Article  CAS  Google Scholar 

  3. Lee, C.Y. & Chiappinelli, V.A. Similarity of endothelin to snake-venom toxin. Nature 335, 303 (1988).

    Article  CAS  Google Scholar 

  4. Takasaki, C., Yanagisawa, M., Kimura, S., Goto, K. & Masaki, T. Similarity of endothelin to snake-venom toxin. Nature 335, 303 (1988).

    Article  Google Scholar 

  5. Kochva, E., Viljoen, C.C. & Botes, D.P. A new type of toxin in the venom of snakes of the genus Atractaspis (Atractaspidinae). Toxicon 20, 581–592 (1982).

    Article  CAS  Google Scholar 

  6. Takasaki, C., Tamiya, N., Bdolah, A., Wollberg, Z. & Kochva, E. Sarafotoxins S6: several isotoxins from Atractaspis engaddensis (burrowing asp) venom that affect the heart. Toxicon 26, 543–548 (1988).

    Article  CAS  Google Scholar 

  7. Becker, A. et al. Bibrotoxin, a novel member of the endothelin sarafotoxin peptide family, from the venom of the burrowing asp atractaspis-bibroni. FEBS Lett. 315, 100–103 (1993).

    Article  CAS  Google Scholar 

  8. Itoh, Y. et al. Cloning and sequence analysis of cDNA encoding the precursor of a human endothelium-derived vasoconstrictor peptide, endothelin: identity of human and porcine endothelin. FEBS Lett. 231, 440–444 (1988).

    Article  CAS  Google Scholar 

  9. Arai, H., Hori, S., Aramori, I., Ohkubo, H. & Nakanishi, S. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348, 730–732 (1990).

    Article  CAS  Google Scholar 

  10. Lin, H.Y., Kaji, E.H., Winkel, G.K., Ives, H.E. & Lodish, H.F. Cloning and functional expression of a vascular smooth muscle endothelin 1 receptor. Proc. natn. Acad. Sci. U.S.A. 88, 3185–3189 (1991).

    Article  CAS  Google Scholar 

  11. Hosoda, K. et al. Cloning and expression of human endothelin-1 receptor cDNA. FEBS Lett. 287, 23–26 (1991).

    Article  CAS  Google Scholar 

  12. Sakurai, T. et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348, 732–735 (1990).

    Article  CAS  Google Scholar 

  13. Nakamuta, M. . et al. Cloning and sequence analysis of a cDNA encoding human non-selective type of endothelin receptor. Biochem. biophys. Res. Commun. 177, 34–39 (1991).

    Article  CAS  Google Scholar 

  14. Ogawa, Y., Nakao, K., Arai, H., Nakanishi, S., & Imura, H. Molecular cloning of a non-isopeptide-selective human endothelin receptor. Biochem. biophys. Res. Commun. 178, 248–255 (1991).

    Article  CAS  Google Scholar 

  15. Kimura, S. et al. Structure-activity relationships of endothelin:importance of the C-terminal moiety. Biochem. biophys. Res. Commun. 156, 1182–1186 (1988).

    Article  CAS  Google Scholar 

  16. Nakajima, K. et al. Structure-activity relationships of endothelin:importance of charged groups. Biochem. Biophys. Res. Commun. 163, 424–429 (1989).

    Article  CAS  Google Scholar 

  17. Spinella, M.J., Malik, A.B., Everitt, J. & Andersen, T.T. Design and synthesis of a specific endothelin 1 antagonist: effects on pulmonary vasoconstriction. Proc. natn. Acad. Sci. U.S.A. 88, 7443–7446 (1991).

    Article  CAS  Google Scholar 

  18. Panek, R.L. et al. Importance of secondary structure for endothelin binding and functional activity. Biochem. biophys. Res. Commun. 183, 572–576 (1992).

    Article  CAS  Google Scholar 

  19. Filep, J.G., Rousseau, A., Fournier, A. & Sirois, P. Structure-activity relationship of analogues of endothelin-1: dissociation of hypotensive and pressoractions. Eur. J. Pharmacol. 220, 263–266 (1992).

    Article  CAS  Google Scholar 

  20. Panek, R.L. et al. Endothelin and structurally related analogs distinguish between endothelin receptor subtypes. Biochem. biophys. Res. Commun. 183, 566–571 (1992).

    Article  CAS  Google Scholar 

  21. Molenaar, P., Kuc, R.E. & Davenport, A.P. Characterization of two new ETB selective radioligands, [125l]-BQ3020 and [125l]-[Ala 1,3,11,15]ET-1 in human heart. Br. J. Pharmacol. 107, 637–639 (1992).

    Article  CAS  Google Scholar 

  22. Saeki, T., Ihara, M., Fukuroda, T., Yamagiwa, M. & Yano, M. [Ala 1,3,1l,15]endothelin-1 analogs with ETB agonist activity. Biochem. biophys. Res. Commun. 179, 286–292 (1992).

    Article  Google Scholar 

  23. de Castiglione, R. et al. Alanine scan of endothelin. in Peptides Chemistry and Biology (eds Smith, J.A. & Rivier, J.E.) 402–403 (ESCOM, Leiden, 1992).

    Google Scholar 

  24. Huggins, J.P., Pelton, J.T. & Miller, R.C. The structure and specificity of endothelin receptors: their importance in physiology and medicine. Pharmac. Ther. 59, 55–123 (1993).

    Article  CAS  Google Scholar 

  25. Takasaki, C. et al. Structure-activity relationships of sarafotoxins: chemical syntheses of chimera peptides of sarafotoxins S6b and S6c. Eur. J. Pharmacol. 198, 165–169 (1991).

    Article  CAS  Google Scholar 

  26. Krystek, S.R. Jr, et al. Conformation of endothelin in aqueous ethylene glycol determined by 1H-NMR and molecular dynamics simulations. FEBS Lett. 281, 212–218 (1991).

    Article  CAS  Google Scholar 

  27. Andersen, N.H., Chen, C., Marschner, T.M., Krystek, S.R. Jr & Bassolino, D. Conformational isomerism of endothelin in acidic aqueous media: a conformational NOESY analysis. Biochemistry 31, 1280–1295 (1992).

    Article  CAS  Google Scholar 

  28. Saudek, V., Hoflack, J. & Pelton, J.T. 1H-NMR study of endothelin, sequence-specific assignment of the spectrum and a solution structure. FEBS Lett. 257, 145–148 (1989).

    Article  CAS  Google Scholar 

  29. Endo, S. et al. Solution conformation of endothelin determined by nuclear magnetic resonance and distance geometry. FEBS Lett. 257, 149–154 (1989).

    Article  CAS  Google Scholar 

  30. Bortmann, P., Hoflack, J., Pelton, J.T. & Saudek, V. Solution conformation of endothelin-3 by 1H NMR and distance geometry calculations. Neurochem Int. 18, 491–496 (1991)

    Article  CAS  Google Scholar 

  31. Mills, R.G., O'Donoghue, S.I., Smith, R. & King, G.F. Solution structure of endothelin-3 determined using NMR spectroscopy. Biochemistry 31, 5640–5445 (1992).

    Article  CAS  Google Scholar 

  32. Munro, S. et al. Solution conformation of endothelin, a potent vaso-constricting bicyclic peptide. A combined use of (H)1 NMR and distance geometry calculations. FEBS Lett. 278 9–13 (1991).

    Article  CAS  Google Scholar 

  33. Reily, M.D. & Dunbar, J.B. Jr The conformation of endothelin-1 in aqueous solution: NMR-derived constraints combined with distance geometry and molecular dynamics calculations. Biochem. biophys. Res. Commun. 178, 570–577 (1991).

    Article  CAS  Google Scholar 

  34. Tamaoki, H. et al. Solution conformation of endothelin determined by means of 1H NMR spectroscopy and distance geometry calculations. Prot. Engng. 4, 509–518 (1991).

    Article  CAS  Google Scholar 

  35. Anderson, N.H., Cao, B. & Chen, C. Peptide/protein structure analysis using chemical shift index method: upfield α-CH values reveal dynamic helices and αL sites. Biochem. biophys. Res. Commun. 184, 1008–1014 (1992).

    Article  Google Scholar 

  36. Aumelas, A. et al. Determination of the structure of [Nle7]-endothelin by 1H NMR. Int. J. Peptide Protein Res. 37, 315–324 (1991).

    Article  CAS  Google Scholar 

  37. Dalgarno, D.C., Slater, L., Chackalamannil, S. & Senior, M.M. Solution conformation of endothelin and point mutants by nuclear magnetic resonance spectroscopy. Int. J. Peptide Protein Res. 40, 515–523 (1992).

    Article  CAS  Google Scholar 

  38. Aumelas, A. et al. 1H NMR study of the solution structure of sarafotoxin-S6b. Neurochem. Int. 18, 471–475 (1991).

    Article  CAS  Google Scholar 

  39. Lee, B. & Richards, F.M. The interpretation of protein structures: estimation of static accessibility. J. molec. Biol. 55, 379–400 (1971).

    Article  CAS  Google Scholar 

  40. Spinella, M.J. et al. A proposed structural model of endothelin. Peptide Res. 2, 286–291 (1989).

    CAS  Google Scholar 

  41. Menziani, M.C. et al. A theoretical study of the structure of big endothelin. J. chim. phys. et phys.-chim. Biol. 88, 2687–2694 (1991).

    Article  CAS  Google Scholar 

  42. Pease, J.H.B. & Wemmer, D.E. Solution structure of apamin determined by nuclear magnetic resonance and distance geometry. Biochemistry 27, 8491–8498 (1988).

    Article  CAS  Google Scholar 

  43. Kumar, N.V., Wemmer, D.E. & Kallenbach, N.R. Structure of P401 (mast-cell degranulating peptide) in solution. Biophys. Chem. 31, 113–119 (1988).

    Article  CAS  Google Scholar 

  44. Perkins, T.D.J., Hider, R.C. & Barlow, D.J. Proposed solution structure of endothelin. Int. J. Peptide Protein Res. 36, 128–133 (1990).

    Article  CAS  Google Scholar 

  45. Kobayashi, Y. et al. A new -helical motif in membrane active peptides. Neurochem. Int. 18, 525–534 (1991).

    Article  CAS  Google Scholar 

  46. Almassy, R.J., Fontecilla-Camps, J.C., Suddath, F.L. & Bugg, C.E. Structure of variant–3 scorpion neurotoxin from Centroides sculturatus ewing, refined at 1. 8 Å resolution. J. molec. Biol. 170, 497–527 (1983).

    Article  CAS  Google Scholar 

  47. Waller, D. et al. Crystallization and preliminary X-ray analysis of human endothelin. Acta crystallogr. B48, 239–240 (1992).

    Article  CAS  Google Scholar 

  48. Peapus, D.H., Janes, R.W. & Wallace, B.A. Preliminary crystallization and X-ray analysis of orthorhombic human endothelin. J. molec. Biol. 234, 1250–1252 (1993).

    Article  CAS  Google Scholar 

  49. Matthews, B.W. Solvent content of protein crystals. J. molec. Biol. 33, 491–497 (1968).

    Article  CAS  Google Scholar 

  50. Pelton, J.T. Fluorescence studies of endothelin-1. Neurochem. Int. 18, 485–489 (1991).

    Article  CAS  Google Scholar 

  51. Leslie, A.G.W. Recent changes to the MOSFLM package for processing film and image plate data. CCP4 andESF-EACMB Newsletter on Protein Crystallography. 26 (1992).

  52. Haneef, I., Moss, D.S., Stanford, M.J. & Borkakoti, N. Restrained structure-factor least-squares refinement using a vector processing computer. Acta crystallogr. A41, 426–433 (1985).

    Article  CAS  Google Scholar 

  53. Jones, T.A. Interactive computer graphics: FRODO. Meth. Enzym. 115, 157–171 (1985).

    Article  CAS  Google Scholar 

  54. Brunger, A.T. Crystallographic refinement by simulated annealing. Application to a 2.8-A resolution structure of aspartate aminotransferase. J. molec. Biol. 203, 803–816 (1988).

    Article  CAS  Google Scholar 

  55. Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. PROCHECK - A program to check the stereochemical quality of protein structures. J. app. Crystallogr. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

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  1. Diane H. Peapus

    Present address: Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York, 12180, USA

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  1. Department of Crystallography, Birkbeck College, University of London, London, WC1E 7HX, UK

    Robert W. Janes & B.A. Wallace

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Janes, R., Peapus, D. & Wallace, B. The crystal structure of human endothelin. Nat Struct Mol Biol 1, 311–319 (1994). https://doi.org/10.1038/nsb0594-311

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