Abstract
Steroid hormones play a vital role in a wide variety of essential physiological processes including cell growth, sexual development, maintenance of salt balance and sugar metabolism. Because of the key role that steroids play in human health and disease therapy, an understanding of the molecular details of steroid hormone action is essential. Small changes in the number and position of functional groups on the steroid nucleus result in large differences in activity. Many of these processes are known to be dependent upon initial binding of the steroid to a specific cytosolic protein receptor and the subsequent interaction of the steroid-receptor complex with chromatin [1]. An examination of the three-dimensional shapes of the hormones, antihormones, chemicals and the drugs that compete for a common binding site on a specific receptor binding protein or metabolizing enzyme can provide information on structural features that influence hormonal response. Crystallographic data on over 1000 steroids [2,3] provide information concerning preferred conformations, relative stabilities and substituent influence on the interactive potential of steroid hormones and analogs. Systematic conformational analysis of subsets of these data having common structural features suggests that steroids crystallize in global minimum energy conformations or local minimum energy conformations that are less than two kcal mol-1 above the global minimum [4–6]
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Evans, R. M., (1988) The steroid and thyroid hormone receptor superfamily Science 240, 889–895.
Duax, W. L. and Norton, D. A. (1975) Atlas of Steroid Structure, Vol. 1, Plenum, New York.
Griffin, J. F., Duax, W. L. and Weeks, C. M. (1984) Atlas of Steroid Structure, Vol. 2, Plenum, New York.
Duax, W. L., Weeks, C. M. and Rohrer, D. C. (1976) Crystal structures of steroids, in E.L. Eliel and N.L. Allinger (eds.) Topics in Stereochemistry, Wiley-Interscience, New York, pp. 271–383.
Duax, W. L., Griffin, J. F. and Rohrer, D. C. (1981) Conformation of the progesterone side chain: Conflict between X-ray data and force field calculations, J. Am. Chem. Soc. 103, 6705–6712.
Duax, W. L., Fronckowiak, M. D., Griffin, J. F. and Rohrer, D. C. (1982) A comparison between crystallographic data and molecular mechanics calculations on the side chain and backbone conformations of steroids, in J. Jortner and B. Pullman (eds.) Intramolecular Dynamics, D. Reidel, Dordrecht, pp. 505–524.
Duax, W. L., Cody, V., Griffin, J. F., Rohrer, D. C. and Weeks, C. (1978) Molecular conformation and protein binding affinity of progestins J. Tox. Env. Health 4, 204–227.
Duax, W. L. and Griffin, J. F. (1987) Structural features which distinghish estrogen agonists and antagonists J. Ster. Biochem. 27, 271–280.
Duax, W. L., Griffin, J. F., Rohrer, D. C., Swenson, D. C. and Weeks, C. M. (1981) Molecular details of receptor binding and hormone action of steroids derived from X-ray crystallographic investigations, in J. R. Pasqualini and G. Perez-Palacios (eds) Recent Advances in Steroid Biochemistry, J. Ster. Biochem., Pergamon Press Ltd., New York, Vol. 15, pp. 41–47.
Duax, W. L. and Griffin, J. F. (1989) The structure and receptor binding of steroid hormones, in B. Testa (ed.) Advances in Drug Research, Academic Press, New York, pp. 115–138.
Duax, W. L., Griffin, J. F., Weeks, C. M. and Wawrzak, Z., (1988) The mechanism of action of steroid antagonists: Insights from crystallographic studies J. Ster. Biochem. 31, 481–492.
Kirchhoff, J., Soffie, M. and Rousseau, G. G. (1979) Differences in the steroid-binding site specificities of rat prostate androgen receptor and epididymal androgen-binding protein J. Ster. Biochem. 10, 487–497.
Noteboom, W. D. and Gorski, J. (1966) Stereospecific binding of estrogens in the rat uterus J. Arch. Biochim. Biophys. III, 559.
Binart, N., Catelli, M. G., Geynet, C., Puri, V., Hanel, R., Mester, J. and Baulieu, E. E., (1979) Monohydroxy-tamoxifen: and antiestrogen with high affinity for the chick oviduct oestrogen receptor Biochem. Bipophys. Res. Comm. 91, 812–818.
Mirocha, C. J., Christensen, C. M. and Nelson, G. H. (1965) Physiologic activity of some fungal estrogens produced by fusariumCancer Res. 28, 2319–2372.
Mueller, G. and Kim, U.-H. (1978) Displacement of estradiol from estrogen receptors by simple alkyl phenols Endocrinology, 102, 1429–1435.
Duax, W. L., Cody, V., Griffin, J. F., Rohrer, D. C., Weeks, C. M. (1978) Molecular conformation and protein binding affinity of progestins J. Tox. Env. Health 4, 205–227.
Duax, W. L. and Weeks, C. M. (1980) Molecular basis for estrogenicity; X-ray crystallographic studies, in J. A. McLachlan (ed.), Estrogens in the Environment, Elsevier, New York, pp. 11–31.
Duax, W. L., Griffin, J. F., Weeks, C. M. and Korach, K. S. (1985), Molecular conformation, receptor binding, and hormone action of natural and synthetic estrogens and antiestrogens, in: J. McKinney (ed.), Environmental Health Perspectives, Elsevier, New York,, Vol. 61, pp. 111–121.
Borgna, J. L., Coezy, E. and Rochefort, H. (1982) Mode of action of LN1643 (a triphenylbromoethylene antiestrogen) probable mediation by the estrogen receptor and high affinity metabolite Biochem. Pharmacol. 31, 3187–3191.
Durani, S., Agarwal, A. K., Saxena, R., Setty, B. S., Gupta, R. C., Kole, P. L., Ray, S. and Anand, N. (1979) Seco-oestradiols and some non-steroidal oestrogens: structural correlates of oestrogenic action J. Ster. Biochem. 11, 67–77.
Duax, W. L., Griffin, J. F., Rohrer, D. C., Swenson, D. C. and Weeks, C. M.(1981) Molecular details of receptor binding and hormone action of steroids derived from X-ray crystallographic investigations, in J. R. Pasqualini and G. Perez-Palacios (eds) Recent Advances in Steroid Biochemistry, J. Ster. Biochem., Pergamon Press Ltd., New York, Vol.15, pp. 41–47.
Pons, M., Michel, F., Crastes De Paulet, A., Gilbert, J., Miquel, J. F., Precigoux, G., Hospital, M., Ojasoo, T. and Raynaud, J. P. (1984) Influence of new hydroxylated triphenylethylene (TPE) derivatives or estradiol binding to native cytosol J. Ster. Biochem. 20, 137–145.
Raynaud, J. P., Ojasoo, T., Bouton, M. M. and Philibert, D. (1979) Receptor binding as a tool in the development of new bioactive steroids in Drug Design, Ariens, E. J. (Ed.), Academic Press, New York,, Vol. 8 pp. 169–214.
Terenius, L. (1974) Affinities of progestogen and estrogen receptors in rabbit uterus for synthetic progestins Steroids 23, 909–918.
Kontula, K., Janne, O., Vijko, R., de Jager, E., de Visser, J. and Zeelan, F. (1975) Progesterone-binding proteins: in vitro binding and biological activity of different steroidal ligands Acta Endocr. 78, 574–592.
Smith, H. E., Smith, R. G., Toft, D. O., Neegaard, J. R., Burrows, E. P. and O’Malley, B. W. (1974) Binding of steroids to progesterone receptor proteins in chick oviduct and human uterus J. Biol. Chem. 249, 5924–5932.
Duax, W. L., Cody, V., Griffin, J., Hazel, J. and Weeks, C. M. (1978) Steroid structure and function-II. Conformational transmission and receptor binding of medroxyprogesterone acetate J. Ster. Biochem. 9, 901–907.
Precigoux, G., Busetta, B., Courseille, C. and Hospital, M. (1975) Structure cristalline et moleculaire de la nor-19 testosterone Acta Cryst. B31, 1527–1532.
Sakiz, E., Euvrard, C. and Baulieu, E. E. in F. Lobrie, L. Proulx, (eds.), Endocrinology, Elsevier, Amsterdam, pp. 239ff.
Neef, G., Beier, S., Elger, W., Henderson, D. and Wiechert, R., (1984) New steroids with antiprogestational and antiglucocorticoid activities Steroids 44, 349–372.
van Geerestein, F. J., Kanters J. A., van der Sluis, P., Kroon, J. (1986) Structure of the n-butyl acetate solvate of 11[β-[4-(dimethylamino)phenyl]-17β-hydroxy-17α-(1-propynyl)estra-4,0-dien-3-one Acta Cryst. C42, 1521–1523.
van Geerestein, F. J., Kanters, J. A., Kroon, J. (1987) Structure of 11β-[4-(dimethylamino)phenyl]-17α-(2-propenyl)-estra-4,9-dien-3-one Acta Cryst., C43, 319–322.
Evans, R. M. (1988) The steroid and thyroid hormone receptor superfamily Science 240, 889.
Wahli, W., Martinex, E. (1991) Superfamily of steroid nuclear receptors: positive and negative regulators of gene expression FASEB J. 5, 2243.
Formstecher, P., Lefebvre, P. and Dautrevaux, M. (1988) RU 486 stabilizes the glucocorticoid receptor in a non-transormed high molecular weight form in intact thymus cells under physiological conditions J. Ster. Biochem., 31, 607.
Guiochon-Mantel, A., Loosfelt, H., Ragot, T., Bailly, A., Atger, M., Misrahi, M., Perricaudet, M. and Milgrom, E. (1988) Receptors bound to antiprogestin form abortive complexes Nature, 336, 695.
Willmann, T. and Beato, M. (1986) Steroid-free glucocorticoid receptor binds specifically to mouse mammary tumour virus DNANature 324, 688.
Schauer, M., Chalepakis, G., Willmann, T. and Beato, M. (1989) Binding of hormone accelerates the kinetics of glucocorticoid and progesterone receptor binding to DNA Proc. Natl. Acad. Sci. USA 86, 1123.
Luisi, B. F., Xu, W. X., Otwinowski, Z., Freedman, L. P., Yamamoto, K. R. and Sigler, P. B. (1991) Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA Nature 352, 497–505.
Renard, J-P., Rochel, N., Ruff, M., Vivat, V., Chambon, P., Gronemeyer, H. and Moras, D. (1995) Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid Nature 378, 681.
Bourquet, W., Ruff, M., Chambon, P., Gronemeyer, H. and Moras, D. (1995) Crystal structure of the ligand-binding domain of the human nuclease receptor RXR-α Nature, 385, 377.
Wagner, R. L., Apriletti, J. W., McGrath, M. E., West, B. L., Baxter, J. D. and Fletterick, R. J.(1995) A structural role for hormone in the thyroid hormone receptor Nature 378, 690–697.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Duax, W.L., Griffin, J.F. (1998). Steroid Hormone Structure, Receptor Binding and Activity: Empirical Drug Design. In: Codding, P.W. (eds) Structure-Based Drug Design. NATO ASI Series, vol 352. Springer, Dordrecht. https://doi.org/10.1007/978-94-015-9028-0_1
Download citation
DOI: https://doi.org/10.1007/978-94-015-9028-0_1
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-5078-6
Online ISBN: 978-94-015-9028-0
eBook Packages: Springer Book Archive