Advertisement

Evidence for the Zipper Model in Tachykinin Receptor Binding

  • G. C. Landis
  • B. S. Wire
  • T. F. Burks
  • D. L. Kreulen
  • V. J. Hruby
Conference paper

Abstract

The kinetic effects of conformational selection will depend on the mechanism by which substance P (SP) binds to its receptor. There are two contrasting models which have been proposed for SP: (1) the ‘zipper’ model1; and (2) the ‘lock-and-key’ model2. To understand the binding mechanism in more detail, conformationally constrained analoqs involving the 5–11, 6–11, 5–9, and 5–10 segments were previously designed1,3,4,5 to duplicate the proposed conformation necessary for binding and signal transduction6,7,8,9. We now have prepared several restricted analogs to allow the 5–8 segment of SP free rotation while restricting the 9–11 C-terminal segment. These analogs demonstrate increased activity in the guinea pig ileum when compared to a previous series of analogs which were restricted from the Gln5 (or Gln6) position to the Met11 position1. Also, these analogs did not demonstrate any antagonist activity on the guinea pig ileum against SP or SK at 10 μM.

Keywords

Contrasting Model Zipper Model Conformational Selection Male Hartley Guinea Restricted Analog 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Darman PS, Landis GC, Smits JR, Hirninq LD, Gulya K, Yamamura HI, Burks TF, Hruby VJ (1985) Conformationally restricted cyclic analogs of substance P. Biochem Biophys Res Commun 127(2):656–662PubMedCrossRefGoogle Scholar
  2. 2.
    Cotrait M, Hospital M (1982) Conformational studies on substance P C-term.inal pentapeptide pGlu-PhePhe-Gly-Leu-Met-NH2. Biochem Biophys Res Comm 109(4) :1123–1128PubMedCrossRefGoogle Scholar
  3. 3.
    Chassaing G, Lavielle S, Plorin O, Julien S, Convers O, Marquet A, Beaujorean JC, Torrens Y, Glowinski J (1984) Biological and conformational studies of cyclic analogs of substance P. In: Ulf Ragnarsson (ed) Peptides 1984. Uppsala: Almquist and Wiksell, pp. 345–348Google Scholar
  4. 4.
    Sandberq BEB, Bishai WR, Hannah P (1984) Synthesis of cyclic analogues based on substance P. In: Ulf Ragnarsson (ed). Peptides 1984. Uppsala: Almquist and Wiksell pp. 369–372Google Scholar
  5. 5.
    Theodoropoulos D, Poulos C, Gatos D, Cordopatis P, Escher E, Mizrahi J, Reqoli D, Dalietos D, Furst A, Lee T (1985) Conformationally restricted C-terminal peptides of Substance P. Synthesis, mass spectral analysis and pharmacoloqical properties. J Hed Chern 28:1536–1539Google Scholar
  6. 6.
    Sandberq BEB, Iverson LL (1982) Substance P. J Med Chem 25:1009–1015Google Scholar
  7. 7.
    Manavalan P, Momany FA (1982) Conformation energy calculation on SP. Int J Pep Prot Res 20:357–365Google Scholar
  8. 8.
    Miyoski M, Sugano H (1974) Structureactivity relationship of elodoisin analogs with modified amide bond. In: Wolman Y (ed). Peptides 1974, New York: John Wiley and Sons.Google Scholar
  9. 9.
    Berier JL, Henichart JP, Helbecque N (1984) Conformation of physalamin. Eur J Biochem 142:371–377CrossRefGoogle Scholar
  10. 10.
    Fournier A, Couture R, Magnan J, Gendreau M, Regoli D, St. Pierre S (1980) Synthesis of peptides by solid phase method. V. Substance P and analogs. Can J Biochem 58:272–280Google Scholar
  11. 11.
    Hruby VJ (1982) Conformational res tictions of biologically active peptides via amino acid side chain groups. Life Sci 31:189–199PubMedCrossRefGoogle Scholar
  12. 12.
    Stewart JM, Young. JD (1984) Solid phase peptide synthesis. 2nd ed. Pierce Chemical Co., Pp. 116Google Scholar
  13. 13.
    Tregar G, Nicoll H, Potts J, Leeman S, Chang M (1971) Synthesis of Substance P. Nature New BioI 232: 87–88Google Scholar
  14. 14.
    Porschke D, Eigen M (1965) Co-operative Non-enzymatic base recoqnition J Mol Bio 62:361–381CrossRefGoogle Scholar
  15. 15.
    Burgen ASV, Roberts GCK, Feeney J (1975) Binding of flexible liqands to macromolecules. Nature 253:753–755PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1987

Authors and Affiliations

  • G. C. Landis
    • 1
  • B. S. Wire
    • 1
  • T. F. Burks
    • 1
  • D. L. Kreulen
    • 1
  • V. J. Hruby
    • 1
  1. 1.Departments of Chemistry and PharmacologyUniversity of ArizonaTucsonUSA

Personalised recommendations