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. 1977 Apr;74(4):1373–1377. doi: 10.1073/pnas.74.4.1373

Relative conformational rigidity in oxytocin and (1-penicillamine)-oxytocin: a proposal for the relationship of conformational flexibility to peptide hormone agonism and antagonism.

J P Meraldi, V J Hruby, A I Brewster
PMCID: PMC430763  PMID: 266179

Abstract

A comparative study of the proton and carbon-13 nuclear magnetic resonance spectral parameters of the peptide hormone oxytocin and of its competitive inhibitor [1-L-penicillamine]oxytocin has been made, and the results analyzed in terms of comparative conformational and dynamic properties. The results indicate that oxytocin has a flexible conformation, while [1-L-penicillamine]oxytocin has a more restricted conformation. The results provide a framework for understanding the mechanism of peptide hormone agonism and antagonism for these compounds, and an approach for understanding some features of the interaction of the hormone and related compounds with their receptor.

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Selected References

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

  1. Brewster A. I., Hruby V. J. 300-MHz nuclear magnetic resonance study of oxytocin aqueous solution: conformational implications. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3806–3809. doi: 10.1073/pnas.70.12.3806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brewster A. I., Hruby V. J., Glasel J. A., Tonelli A. E. Proposed conformations of oxytocin and selected analogs in dimethyl sulfoxide as deduced from proton magnetic resonance studies. Biochemistry. 1973 Dec 18;12(26):5294–5304. doi: 10.1021/bi00750a012. [DOI] [PubMed] [Google Scholar]
  3. Burgen A. S., Roberts G. C., Feeney J. Binding of flexible ligands to macromolecules. Nature. 1975 Feb 27;253(5494):753–755. doi: 10.1038/253753a0. [DOI] [PubMed] [Google Scholar]
  4. Chan W. Y., Hruby V. J., Du Vigneaud V. Effects of magnesium ion and oxytocin inhibitors on the uterotonic activity of oxytocin and prostaglandins E2 and F2ALPHA. J Pharmacol Exp Ther. 1974 Jul;190(1):77–87. [PubMed] [Google Scholar]
  5. Deslauriers R., Komoroski R. A., Levy G. C., Paiva A. C., Smith I. C. Conformational heterogeneity in linear peptides in solution: a carbon-1 3 NMR study of (Pro3, Pro5)-angiotensin-II. FEBS Lett. 1976 Feb 1;62(1):50–56. doi: 10.1016/0014-5793(76)80014-2. [DOI] [PubMed] [Google Scholar]
  6. Deslauriers R., Smith C. P., Walter R. Conformational flexibility of the neurohypophyseal hormones oxytocin and lysine-vasopressin. A carbon-13 spin-lattice relaxation study of backbone and side chains. J Am Chem Soc. 1974 Apr 3;96(7):2289–2291. doi: 10.1021/ja00814a071. [DOI] [PubMed] [Google Scholar]
  7. Dyckes D. F., Nestor J. J., Jr, Ferger M. F., Du Vigneaud V., Chan W. Y. (1-beta-mercapto-beta,beta-diethylpropionic acid,4-leucine)-8-lysine-vasopressin and (1-beta-mercapto-beta,beta-diethylpropionic acid,4-leucine)oxytocin, compounds possessing antihormonal properties. J Med Chem. 1974 Sep;17(9):969–972. doi: 10.1021/jm00255a012. [DOI] [PubMed] [Google Scholar]
  8. Feeney J., Roberts G. C., Rockey J. H., Burgen A. S. Conformational studies of oxytocin and lysine vasopressin in aqueous solution using high resolution NMR spectroscopy. Nat New Biol. 1971 Jul 28;232(30):108–110. doi: 10.1038/newbio232108a0. [DOI] [PubMed] [Google Scholar]
  9. Ganellin C. R. Conformation of histamine derivatives. 3. A relationship between conformation and pharmacological activity. J Med Chem. 1973 Jun;16(6):620–623. doi: 10.1021/jm00264a009. [DOI] [PubMed] [Google Scholar]
  10. Gibbons W. A., Némethy G., Stern A., Craig L. C. An approach to conformational analysis of peptides and proteins in solution based on a combination of nuclear magnetic resonance spectroscopy and conformational energy calculations. Proc Natl Acad Sci U S A. 1970 Sep;67(1):239–246. doi: 10.1073/pnas.67.1.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Glasel J. A., Hruby V. J., McKelvy J. F., Spatola A. F. Deuteron magnetic resonance studies on the microdynamical behavior of partially deuterated oxytocin with neurophysin. J Mol Biol. 1973 Sep 25;79(3):555–575. doi: 10.1016/0022-2836(73)90406-3. [DOI] [PubMed] [Google Scholar]
  12. Glickson J. D., Rowan R., Pitner T. P., Dadok J., Bothner-By A. A., Walter R. 1H nuclear magnetic resonance double resonance study of oxytocin in aqueous solution. Biochemistry. 1976 Mar 9;15(5):1111–1119. doi: 10.1021/bi00650a025. [DOI] [PubMed] [Google Scholar]
  13. Honig B., Kabat E. A., Katz L., Levinthal C., Wu T. T. Model-building of neurohypophyseal hormones. J Mol Biol. 1973 Oct 25;80(2):277–295. doi: 10.1016/0022-2836(73)90173-3. [DOI] [PubMed] [Google Scholar]
  14. Jard S., Bockaert J. Stimulus-response coupling in neurohypophysial peptide target cells. Physiol Rev. 1975 Oct;55(4):489–536. doi: 10.1152/physrev.1975.55.4.489. [DOI] [PubMed] [Google Scholar]
  15. Kotelchuck D., Scheraga H. A., Walter R. Conformational energy studies of oxytocin and its cyclic moiety. Proc Natl Acad Sci U S A. 1972 Dec;69(12):3629–3633. doi: 10.1073/pnas.69.12.3629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mabrey S., Klotz I. M. Conformation of gonadotropin releasing hormone. Biochemistry. 1976 Jan 13;15(1):234–242. doi: 10.1021/bi00646a035. [DOI] [PubMed] [Google Scholar]
  17. Meraldi J. P., Hruby V. J. Letter: Studies on the molecular association of oxytocin and related compounds in dimethyl sulfoxide. J Am Chem Soc. 1976 Sep 29;98(20):6408–6410. doi: 10.1021/ja00436a069. [DOI] [PubMed] [Google Scholar]
  18. Nestor J. J., Jr, Ferger M. F., du Vigneaud V. [1-Beta-mercapto-beta,beta-pentamethylenepropionic acid]oxytocin, a potent inhibitor of oxytocin. J Med Chem. 1975 Mar;18(3):284–287. doi: 10.1021/jm00237a015. [DOI] [PubMed] [Google Scholar]
  19. Ohnishi M., Urry D. W. Temperature dependence of amide proton chemical shifts: the secondary structures of gramicidin S and valinomycin. Biochem Biophys Res Commun. 1969 Jul 23;36(2):194–202. doi: 10.1016/0006-291x(69)90314-3. [DOI] [PubMed] [Google Scholar]
  20. Richards W. G., Aschman D. G., Hammond J. Conformational flexibility in physiologically active amines. J Theor Biol. 1975 Jul;52(1):223–230. doi: 10.1016/0022-5193(75)90053-3. [DOI] [PubMed] [Google Scholar]
  21. Smyth D. G. On the molecular mechanism of oxytocin action. Biochim Biophys Acta. 1970 Feb 17;200(2):395–403. doi: 10.1016/0005-2795(70)90182-0. [DOI] [PubMed] [Google Scholar]
  22. Takashima H., Hruby V. J., Du Vigneaud V. The synthesis of (1-deamino,4-L-leucine)-oxytocin and (1-deamino,4-L-isoleucine)-oxytocin and some of their pharmacological properties. J Am Chem Soc. 1970 Feb 11;92(3):677–680. doi: 10.1021/ja00706a041. [DOI] [PubMed] [Google Scholar]
  23. Tonelli A. E., Brewster A. I. The conformational characteristics in solution of the cyclic hexapeptide Gly-Gly-D-Ala-D-Ala-Gly-Gly. J Am Chem Soc. 1972 Apr 19;94(8):2851–2854. doi: 10.1021/ja00763a052. [DOI] [PubMed] [Google Scholar]
  24. Upson D. A., Hruby V. J. Synthesis of specifically deuterated S-benzylcysteines and of oxytocin and related diastereomers deuterated in the half-cystine positions. J Org Chem. 1976 Apr 16;41(8):1353–1358. doi: 10.1021/jo00870a014. [DOI] [PubMed] [Google Scholar]
  25. Vavrek R. J., Ferger M. F., Allen G. A., Rich D. H., Blomquist A. T., Du Vigneaud V. Synthesis of three oxytocin analogs related to (1-deaminopenicillamine)oxytocin possessing antioxytocic acitvity. J Med Chem. 1972 Feb;15(2):123–126. doi: 10.1021/jm00272a001. [DOI] [PubMed] [Google Scholar]
  26. Walter R., Prasad K. U., Deslauriers R., Smith I. C. Conformational studies of oxytocin, lysine vasopressin, arginine vasopressin, and arginine vasotocin by carbon-13 nuclear magnetic resonance spectroscopy. Proc Natl Acad Sci U S A. 1973 Jul;70(7):2086–2090. doi: 10.1073/pnas.70.7.2086. [DOI] [PMC free article] [PubMed] [Google Scholar]

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