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Abstract:

The alkylation of amino groups of the mineralocorticoid receptor (MR) with pyridoxal 5′-phosphate or 2,4,6-trinitrobenzenesulphonate (TNBS) under controlled conditions modifies only one lysyl residue, which accounts for a 70% inhibition of steroid binding capacity. The Kd of aldosterone for MR is not affected by the treatment, but the total number of binding sites is greatly decreased. The modified receptor is capable of dynamically conserving its association with the hsp90-based heterocomplex. Importantly, the binding of natural agonists protects the hormone binding capacity of the MR from the inactivating action of alkylating agents. In contrast, antagonistic steroids are totally incapable of providing such protection. Like the antagonistic ligands, and despite its potent mineralocorticoid biological effect, the sole MR specific synthetic agonist known to date, 11,19-oxidoprogesterone (11-OP), shows no protective effect upon treatment of the MR with pyridoxal 5′-phosphate or TNBS. Limited digestion of the MR with α-chymotrypsin generates a 34 kDa fragment, which becomes totally resistant to digestion upon binding of natural agonists, but not upon binding of antagonists. Interestingly, the synthetic 21-deoxypregnanesteroid 11-OP exhibits an intermediate pattern of proteolytic degradation, suggesting that the conformational change generated in the MR is not equivalent to that induced by antagonists or natural agonists. We conclude that in the first steps of activation, the MR changes its conformation upon binding of the ligand. However, the nature of this conformational change depends on the nature of the ligand. The experimental evidence shown in this work suggests that a single lysyl group can determine the hormone specificity of the MR. © 2002 Elsevier Science B.V. All rights reserved.

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Documento: Artículo
Título:Modification of an essential amino group in the mineralocorticoid receptor evidences a differential conformational change of the receptor protein upon binding of antagonists, natural agonists and the synthetic agonist 11,19-oxidoprogesterone
Autor:Piwien-Pilipuk, G.; Kanelakis, K.C.; Ghini, A.A.; Lantos, C.P.; Litwack, G.; Burton, G.; Galigniana, M.D.
Filiación:Department of Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
Department of Pharmacology, University of Michigan Medical School, 1301 Medical Science Research Building III, Ann Arbor, MI 48109-0632, United States
Departamento De Química Orgánica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, 1428 Buenos Aires, Argentina
Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University, Philadelphia, PA 19107, United States
Departamento De Química Biológica, Facultad De Ciencias Exactas Y Naturales, Universidad De Buenos Aires, 1428 Buenos Aires, Argentina
Palabras clave:2,4,6-Trinitrobenzenesulfonate; Aldosterone; hsp90 heterocomplex; Pyridoxal 5′-phosphate; Sodium retention; 11,19 oxidoprogesterone; 21 deoxypregnanesteroid 11,19 oxidoprogesterone; 6,19 oxidoprogesterone; aldosterone; alkylating agent; amino acid; chymotrypsin A; corticosterone; deoxycorticosterone; heat shock protein 90; ligand; lysine; mineralocorticoid antagonist; mineralocorticoid receptor; progesterone derivative; pyridoxal 5 phosphate; receptor protein; spironolactone; testosterone; trinitrobenzenesulfonic acid; unclassified drug; alkylation; animal tissue; article; binding affinity; binding site; chemical modification; conformational transition; controlled study; inhibition kinetics; ligand binding; male; nonhuman; priority journal; protein degradation; rat; receptor binding; steroid binding; Aldosterone; Alkylating Agents; Amines; Animals; Binding Sites; Chymotrypsin; Cytosol; HSP90 Heat-Shock Proteins; Hydrogen-Ion Concentration; Kidney; Male; Progesterone; Protein Conformation; Pyridoxal Phosphate; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Time Factors; Trinitrobenzenesulfonic Acid; Tritium
Año:2002
Volumen:1589
Número:1
Página de inicio:31
Página de fin:48
DOI: http://dx.doi.org/10.1016/S0167-4889(01)00184-7
Título revista:Biochimica et Biophysica Acta - Molecular Cell Research
Título revista abreviado:Biochim. Biophys. Acta Mol. Cell Res.
ISSN:01674889
CODEN:BAMRD
CAS:11,19-oxidoprogesterone, 1913-28-6; Aldosterone, 52-39-1; Alkylating Agents; Amines; chymotrypsin A, EC 3.4.21.-; Chymotrypsin, EC 3.4.21.1; HSP90 Heat-Shock Proteins; Progesterone, 57-83-0; Pyridoxal Phosphate, 54-47-7; Receptors, Mineralocorticoid; Trinitrobenzenesulfonic Acid, 2508-19-2; Tritium, 10028-17-8
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_01674889_v1589_n1_p31_PiwienPilipuk.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01674889_v1589_n1_p31_PiwienPilipuk

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Citas:

---------- APA ----------
Piwien-Pilipuk, G., Kanelakis, K.C., Ghini, A.A., Lantos, C.P., Litwack, G., Burton, G. & Galigniana, M.D. (2002) . Modification of an essential amino group in the mineralocorticoid receptor evidences a differential conformational change of the receptor protein upon binding of antagonists, natural agonists and the synthetic agonist 11,19-oxidoprogesterone. Biochimica et Biophysica Acta - Molecular Cell Research, 1589(1), 31-48.
http://dx.doi.org/10.1016/S0167-4889(01)00184-7
---------- CHICAGO ----------
Piwien-Pilipuk, G., Kanelakis, K.C., Ghini, A.A., Lantos, C.P., Litwack, G., Burton, G., et al. "Modification of an essential amino group in the mineralocorticoid receptor evidences a differential conformational change of the receptor protein upon binding of antagonists, natural agonists and the synthetic agonist 11,19-oxidoprogesterone" . Biochimica et Biophysica Acta - Molecular Cell Research 1589, no. 1 (2002) : 31-48.
http://dx.doi.org/10.1016/S0167-4889(01)00184-7
---------- MLA ----------
Piwien-Pilipuk, G., Kanelakis, K.C., Ghini, A.A., Lantos, C.P., Litwack, G., Burton, G., et al. "Modification of an essential amino group in the mineralocorticoid receptor evidences a differential conformational change of the receptor protein upon binding of antagonists, natural agonists and the synthetic agonist 11,19-oxidoprogesterone" . Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1589, no. 1, 2002, pp. 31-48.
http://dx.doi.org/10.1016/S0167-4889(01)00184-7
---------- VANCOUVER ----------
Piwien-Pilipuk, G., Kanelakis, K.C., Ghini, A.A., Lantos, C.P., Litwack, G., Burton, G., et al. Modification of an essential amino group in the mineralocorticoid receptor evidences a differential conformational change of the receptor protein upon binding of antagonists, natural agonists and the synthetic agonist 11,19-oxidoprogesterone. Biochim. Biophys. Acta Mol. Cell Res. 2002;1589(1):31-48.
http://dx.doi.org/10.1016/S0167-4889(01)00184-7