Abstract:
21-Hydroxy-6,19-epoxyprogesterone (21OH-6,19OP) is a selective antiglucocorticoid that lacks the bulky substituent at C-11 found in active antagonists of the glucocorticoid receptor (GR). Ligand-free GR ligand-binding domain (LBD) and GR LBD complexed with 21OH-6,19OP or the agonist dexamethasone were simulated during 6 ns using molecular dynamics. Results suggest that the time fluctuation and average position adopted by the H1-H3 loop affect the ability of GR LBD-21OH-6,19OP complex to homodimerize, a necessary step in transcriptome assembly. A nuclear localization and a transactivation experiment showed that, although 21OH-6,19OP activates the translocation of the GR, the nuclear complex is unable to induce the transcription of a reporter driven by a promoter, that requires binding to a GR homodimer to be activated. These findings support the hypothesis that the passive antagonist mode of action of 21OH-6,190P resides, at least in part, in the incapacity of the GR-21OH-6,19OP complex to dimerize. © 2008 American Chemical Society.
Registro:
Documento: |
Artículo
|
Título: | Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone |
Autor: | Álvarez, L.D.; Martí, M.A.; Veleiro, A.S.; Presman, D.M.; Estrin, D.A.; Pecci, A.; Burton, G. |
Filiación: | Departamento de Química Orgánica/UMYMFOR-CONICET, Universidad de Buenos Aires, Pabellón 2, Buenos Aires CI428EGA, Argentina Departamento de Quimica Inorganica, Analitica Y Quimica Fisica/INQUIMAE-CONICET, Universidad de Buenos Aires, Pabellón 2, Buenos Aires CI428EGA, Argentina Departamento de Química Biológica/IFIBYNE-CONICET, Universidad de Buenos Aires, Pabellón 2, Buenos Aires CI428EGA, Argentina
|
Palabras clave: | 21 hydroxy 6,19 epoxyprogesterone; dexamethasone; glucocorticoid antagonist; glucocorticoid receptor; homodimer; transcriptome; unclassified drug; animal cell; article; binding affinity; drug mechanism; gene activation; gene location; gene translocation; molecular dynamics; mouse; nonhuman; transactivation; Animals; Binding Sites; Cell Line; Cell Nucleus; Crystallography, X-Ray; Dexamethasone; Dimerization; Genes, Reporter; Ligands; Mice; Microscopy, Confocal; Models, Molecular; Progesterone; Promoter Regions (Genetics); Protein Transport; Receptors, Glucocorticoid; Trans-Activation (Genetics) |
Año: | 2008
|
Volumen: | 51
|
Número: | 5
|
Página de inicio: | 1352
|
Página de fin: | 1360
|
DOI: |
http://dx.doi.org/10.1021/jm800007w |
Título revista: | Journal of Medicinal Chemistry
|
Título revista abreviado: | J. Med. Chem.
|
ISSN: | 00222623
|
CODEN: | JMCMA
|
CAS: | dexamethasone, 50-02-2; 21-hydroxy-6,19-oxidoprogesterone; Dexamethasone, 50-02-2; Ligands; Progesterone, 57-83-0; Receptors, Glucocorticoid
|
Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00222623_v51_n5_p1352_Alvarez |
Referencias:
- Necela, B.M., Cidlowski, J.A., Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells (2004) Proc. Am. Thorac. Soc, 1, pp. 239-246
- Moore, J.T., Collins, J.L., Pearce, K.H., The nuclear receptor superfamily and drug discovery (2006) ChemMedChem, 1, pp. 504-523
- Farman, N., Bocchi, B., Mineralocorticoid selectivity: Molecular and cellular aspects (2000) Kidney Int, 57, pp. 1364-1369
- Wambach, G., Higgins, J.R., Antimineralocorticoid action of progesterone in the rat: Correlation of the effect on electrolyte excretion and interaction with renal mineralocorticoid receptor (1978) Endocrinology, 102, pp. 1686-1693
- Kumar, R., Thompson, E.B., Gene regulation by the glucocorticoid receptor: Structure:function relationship (2005) J. Steroid Biochem. Mol. Biol, 94, pp. 383-394
- Herr, I., Pfitzenmaier, J., Glucocorticoid use in prostate cancer and other solid tumours: Implications for effectiveness of cytotoxic treatment and metastases (2006) Lancet Oncol, 7, pp. 425-430
- Zhang, C., Beckermann, B., Kallifatidis, G., Liu, Z., Rittgen, W., Edler, L., Buchler, P., Herr, I., Corticosteroids induce chemotherapy resistance in the majority of tumour cells from bone, brain, breast, cervix, melanoma and neuroblastoma (2006) Int. J. Oncol, 29, pp. 1295-1301
- Necela, B.M., Cidlowski, J.A., Crystallization of the human glucocorticoid receptor ligand binding domain: A step towards selective glucocorticoids (2003) Trends Pharmacol. Sci, 24, pp. 58-61
- Teutsch, J.G., Costerousse, G., Philibert, D., Deraedt, R., Novel Steroids (1983), U.S. Patent 4,386,085; Spitz, I.M., Bardin, C.W., Mifepristone (RU-486): A modulator of progestin and glucocorticoid action (1993) N. Engl. J. Med, 329, pp. 404-412
- Zhang, J., Tsai, F.T., Geller, D.S., Differential interaction of RU486 with the progesterone and glucocorticoid receptors (2006) J. Mol. Endocrinol, 37, pp. 163-173
- Gronemeyer, H., Gustafsson, J.A., Laudet, V., Principles for modulation of the nuclear receptor superfamily (2004) Nat. Rev. Drug Discov, 3, pp. 950-964
- Bledsoe, R.K., Montana, V.G., Stanley, T.B., Delves, C.J., Apolito, C.J., McKee, D.D., Consler, T.G., Xu, H.E., Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition (2002) Cell, 110, pp. 93-105
- Chen, J.D., Evans, R.M., A transcriptional co-repressor that interacts with nuclear hormone receptors (1995) Nature, 377, pp. 454-457
- Brzozowski, A.M., Pike, A.C., Dauter, Z., Hubbard, R.E., Bonn, T., Engstrom, O., Ohman, L., Carlquist, M., Molecular basis of agonism and antagonism in the oestrogen receptor (1997) Nature, 389, pp. 753-758
- Shiau, A.K., Barstad, D., Loria, P.M., Cheng, L., Kushner, P.J., Agard, D.A., Greene, G.L., The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen (1998) Cell, 95, pp. 927-937
- Shiau, A.K., Barstad, D., Radek, J.T., Meyers, M.J., Nettles, K.W., Katzenellenbogen, B.S., Katzenellenbogen, J.A., Greene, G.L., Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism (2002) Nat. Struct. Biol, 9, pp. 359-364
- Singh, S.M., Gauthier, S., Labrie, F., Androgen receptor antagonists (antiandrogens): Structure-activity relationships (2000) Curr. Med. Chem, 7, pp. 211-247
- Souque, A., Fagart, J., Couette, B., Davioud, E., Sobrio, F., Marquet, A., Rafestin-Oblin, M.E., The mineralocorticoid activity of progesterone derivatives depends on the nature of the C18 substituent (1995) Endocrinology, 136, pp. 5651-5658
- Honer, C., Nam, K., Fink, C., Marshall, P., Ksander, G., Chatelain, R.E., Cornell, W., Schumacher, C., Glucocorticoid receptor antagonism by cyproterone acetate and RU486 (2003) Mol. Pharmacol, 63, pp. 1012-1020
- Weeks, C.M., Duax, W.L., Wolf, M.E., Comparison of the molecular structures of six corticosteroids (1976) J. Am. Chem. Soc, 95, pp. 2865-2868
- Vicent, G.P., Monteserin, M.C., Veleiro, A.S., Burton, G., Lantos, C.P., Galigniana, M.D., 21-Hydroxy-6,19-oxidoprogesterone: A novel synthetic steroid with specific antiglucocorticoid properties in the rat (1997) Mol. Pharmacol, 52, pp. 749-753
- Cadepond, F., Ulmann, A., Baulieu, E.E., RU486 (mifepristone): Mechanisms of action and clinical uses (1997) Annu. Rev. Med, 48, pp. 129-156
- Kauppi, B., Jakob, C., Farnegardh, M., Yang, J., Ahola, H., Alarcon, M., Calles, K., Carlquist, M., The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism (2003) J. Biol. Chem, 278, pp. 22748-22754
- Patel, F.A., Funder, J.W., Challis, J.R., Mechanism of cortisol/progesterone antagonism in the regulation of 15-hydroxyprostaglandin dehydrogenase activity and messenger ribonucleic acid levels in human chorion and placental trophoblast cells at term (2003) J. Clin. Endocrinol. Metab, 88, pp. 2922-2933
- Hillisch, A., von Langen, J., Menzenbach, B., Droescher, P., Kaufmann, G., Schneider, B., Elger, W., The significance of the 20-carbonyl group of progesterone in steroid receptor binding: A molecular dynamics and structure-based ligand design study (2003) Steroids, 68, pp. 869-878
- von Langen, J., Fritzemeier, K.H., Diekmann, S., Hillisch, A., Molecular basis of the interaction specificity between the human glucocorticoid receptor and its endogenous steroid ligand cortisol (2005) ChemBioChem, 6, pp. 1110-1118
- Williams, S.P., Sigler, P.B., Atomic structure of progesterone complexed with its receptor (1998) Nature, 393, pp. 392-396
- Bourguet, W., Ruff, M., Chambon, P., Gronemeyer, H., Moras, D., Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha (1995) Nature, 375, pp. 377-382
- Horwitz, K.B., Zava, D.T., Thilagar, A.K., Jensen, E.M., McGuire, W.L., Steroid receptor analyses of nine human breast cancer cell lines (1978) Cancer Res, 38, pp. 2434-2437
- Beato, M.H., Schütz, P.G., Steroid hormone receptors: Many Actors in search of a plot (1995) Cell, 83, pp. 851-857
- Burton, G, Lantos, C. P, Veleiro, A. S. Method for the preparation of 21-hydroxy-6,19-oxidoprogesterone 21OH-6OP, U.S. Patent 7,071,328, 2006; Veleiro, A.S., Pecci, A., Monteserin, M.C., Baggio, R., Garland, M.T., Lantos, C.P., Burton, G., 6,19-Sulfur-bridged progesterone analogues with antiimmunosuppressive activity (2005) J. Med. Chem, 48, pp. 5675-5683
- Gaussian 03, Revision B.05:Frisch, M. J, Trucks, G. W, Schlegel, H. B, Scuseria, G. E, Robb, M. A, Cheeseman, J. R, Montgomery, J. A, Jr, Vreven, T, Kudin, K. N, Burant, J. C, Millam, J. M, Iyengar, S. S, Tomasi, J, Barone, V, Mennucci, B, Cossi, M, Scalmani, G, Rega, N, Petersson, G. A, Nakatsuji, H, Hada, M, Ehara, M, Toyota, K, Fukuda, R, Hasegawa, J, Ishida, M, Nakajima, T, Honda, Y, Kitao, O, Nakai, H, Klene, M, Li, X, Knox, J. E, Hratchian, H. P, Cross, J. B, Adamo, C, Jaramillo, J, Gomperts, R, Stratmann, R. E, Yazyev, O, Austin, A. J, Cammi, R, Pomelli, C, Ochterski, J. W, Ayala, P. Y, Morokuma, K, Voth, G. A, Salvador, P, Dannenberg, J. J, Zakrzewski, V. G, Dapprich, S, Daniels, A. D, Strain, M. C, Farkas, O, Malick, D. K, Rabuck, A. D, Raghavachari, K, Foresman, J. B, Ortiz, J. V, Cui, Q, Baboul, A. G, Clifford, S, Cioslowski, J, Stefanov, B. B, Liu, G, Liashenko, A, Piskorz, P, Komaromi, I, Martin, R. L, F; Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.S., Cheatham Iii, T.E., DeBolt, S., Ferguson, D., Kollman, P., AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules (1995) Comput. Phys. Commun, 91, pp. 1-41
- Berendsen, H.J.C., Postma, J.P.M., Van Gunsteren, W.F., DiNola, A., Haak, J.R., Molecular dynamics with coupling to an external bath (1984) J. Chem. Phys, 81, pp. 3684-3690
- CheathaIii, T. E.; Cieplak, P.; Kollman, P. A modified version of the Cornell et al. force field with improved sugar pucker phases and helical repeat Biomol. Struct. Dynam. 1999, 16, 845-862; Amadei, A., Linssen, A.B.M., Berendsen, H.J.C., Essential dynamics of proteins (1993) Proteins: Structure, Funct. Genet, 17, pp. 412-425
Citas:
---------- APA ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A. & Burton, G.
(2008)
. Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone. Journal of Medicinal Chemistry, 51(5), 1352-1360.
http://dx.doi.org/10.1021/jm800007w---------- CHICAGO ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., et al.
"Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone"
. Journal of Medicinal Chemistry 51, no. 5
(2008) : 1352-1360.
http://dx.doi.org/10.1021/jm800007w---------- MLA ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., et al.
"Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone"
. Journal of Medicinal Chemistry, vol. 51, no. 5, 2008, pp. 1352-1360.
http://dx.doi.org/10.1021/jm800007w---------- VANCOUVER ----------
Álvarez, L.D., Martí, M.A., Veleiro, A.S., Presman, D.M., Estrin, D.A., Pecci, A., et al. Exploring the molecular basis of action of the passive antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone. J. Med. Chem. 2008;51(5):1352-1360.
http://dx.doi.org/10.1021/jm800007w