Navegar

Colección

Datos Estadísticas

Artículo

Álvarez, L.D.; Dansey, M.V.; Grinman, D.Y.; Navalesi, D.; Samaja, G.A.; Del Fueyo, M.C.; Bastiaensen, N.; Houtman, R.; Estrin, D.A.; Veleiro, A.S.; Pecci, A.; Burton, G. "Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity" (2015) Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 1851(12):1577-1586
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Background Liver X receptors (LXRs) are transcription factors activated by cholesterol metabolites containing an oxidized side chain. Due to their ability to regulate lipid metabolism and cholesterol transport, they have become attractive pharmacological targets. LXRs are closely related to DAF-12, a nuclear receptor involved in nematode lifespan and regulated by the binding of C-27 steroidal acids. Based on our recent finding that the lack of the C-25 methyl group does not abolish their DAF-12 activity, we evaluated the effect of removing it from the (25R)-cholestenoic acid, a LXR agonist. Methods The binding mode and the molecular basis of action of 27-nor-5-cholestenoic acid were evaluated using molecular dynamics simulations. The biological activity was investigated using reporter gene expression assays and determining the expression levels of endogenous target genes. The in vitro MARCoNI assay was used to analyze the interaction with cofactors. Results 27-Nor-5-cholestenoic acid behaves as an inverse agonist. This correlates with the capacity of the complex to better bind corepressors rather than coactivators. The C-25 methyl moiety would be necessary for the maintenance of a torsioned conformation of the steroid side chain that stabilizes an active LXRβ state. Conclusion We found that a 27-nor analog is able to act as a LXR ligand. Interestingly, this minimal structural change on the steroid triggered a drastic change in the LXR response. General significance Results contribute to improve our understanding on the molecular basis of LXRβ mechanisms of action and provide a new scaffold in the quest for selective LXR modulators. © 2015 Elsevier B.V. All rights reserved.

Registro:

Documento: Artículo
Título:Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity
Autor:Álvarez, L.D.; Dansey, M.V.; Grinman, D.Y.; Navalesi, D.; Samaja, G.A.; Del Fueyo, M.C.; Bastiaensen, N.; Houtman, R.; Estrin, D.A.; Veleiro, A.S.; Pecci, A.; Burton, G.
Filiación:Dpto. Química Orgánica, UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
Dpto. Química Biológica, IFIBYNE (UBA-CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
Pamgene International BV, 5211HH Den Bosch, Netherlands
Dpto. Química Inorgánica Analítica y Química Física and INQUIMAE, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
Palabras clave:Cholestenoic acid; Inverse agonism; Liver X receptors; Molecular dynamics; 27 nor 5 cholestenoic acid; carboxyl group; cholesterol; ligand; liver X receptor alpha; liver X receptor beta; methyl group; steroid; unclassified drug; cholestane derivative; cholestenoic acid; liver X receptor; orphan nuclear receptor; Article; conformational transition; gene expression; gene expression assay; in vitro study; ligand binding; molecular dynamics; molecular stability; priority journal; protein conformation; reporter gene; simulation; antagonists and inhibitors; binding site; drug effects; gene expression regulation; genetics; HEK293 cell line; HepG2 cell line; human; metabolism; Binding Sites; Cholestenes; Gene Expression Regulation; HEK293 Cells; Hep G2 Cells; Humans; Ligands; Orphan Nuclear Receptors
Año:2015
Volumen:1851
Número:12
Página de inicio:1577
Página de fin:1586
DOI: http://dx.doi.org/10.1016/j.bbalip.2015.09.007
Título revista:Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Título revista abreviado:Biochim. Biophys. Acta Mol. Cell Biol. Lipids
ISSN:13881981
CODEN:BBMLF
CAS:cholesterol, 57-88-5; Cholestenes; cholestenoic acid; Ligands; liver X receptor; Orphan Nuclear Receptors
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_13881981_v1851_n12_p1577_Alvarez

Referencias:

  • Jakobsson, T., Treuter, E., Gustafsson, J.A., Steffensen, K.R., Liver X receptor biology and pharmacology: New pathways, challenges and opportunities (2012) Trends Pharmacol. Sci., 33, pp. 394-404
  • Tice, C.M., Noto, P.B., Fan, K.Y., Zhuang, L., Lala, D.S., Singh, S.B., The medicinal chemistry of liver X receptor (LXR) modulators (2014) J. Med. Chem., 57, pp. 7182-7205
  • Im, S.S., Osborne, T.F., Liver X receptors in atherosclerosis and inflammation (2011) Circ. Res., 108, pp. 996-1001
  • Viennois, E., Mouzat, K., Dufour, J., Morel, L., Lobaccaro, J.M., Baron, S., Selective liver X receptor modulators (SLiMs): What use in human health? (2012) Mol. Cell. Endocrinol., 351, pp. 129-141
  • Hong, C., Tontonoz, P., Liver X receptors in lipid metabolism: Opportunities for drug discovery (2014) Nat. Rev. Drug Discov., 13, pp. 433-444
  • Gabbi, C., Warner, M., Gustafsson, J.A., Action mechanisms of liver X receptors (2014) Biochem. Biophys. Res. Commun., 446, pp. 647-650
  • Torocsik, D., Szanto, A., Nagy, L., Oxysterol signaling links cholesterol metabolism and inflammation via the liver X receptor in macrophages (2009) Mol. Asp. Med., 30, pp. 134-152
  • Meaney, S., Babiker, A., Lutjohann, D., Diczfalusy, U., Axelson, M., Bjorkhem, I., On the origin of the cholestenoic acids in human circulation (2003) Steroids, 68, pp. 595-601
  • Ogundare, M., Theofilopoulos, S., Lockhart, A., Hall, L.J., Arenas, E., Sjövall, J., Brenton, A.G., Griffiths, W.J., Cerebrospinal fluid steroidomics: Are bioactive bile acids present in brain? (2010) J. Biol. Chem., 285, pp. 4666-4679
  • Song, C., Liao, S., Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha (2000) Endocrinology, 141, pp. 4180-4184
  • Mahanti, P., Bose, N., Bethke, A., Judkins, J.C., Wollam, J., Dumas, K.J., Zimmerman, A.A.M., Schroeder, F.C., Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. Elegans development and lifespan (2014) Cell Metab., 19, pp. 73-83
  • Mooijaart, S.P., Brandt, B.W., Baldal, E.A., Pijpe, J., Kuningas, M., Beekman, M., Zwaan, B.J., Van heemst, D., C. Elegans DAF-12, nuclear hormone receptors and human longevity and disease at old age (2005) Ageing Res. Rev., 4, pp. 351-371
  • Alvarez, L.D., Manez, P.A., Estrin, D.A., Burton, G., The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands (2012) Proteins: Struct. Func. Bioinf., 80, pp. 1798-1809
  • Samaja, G.A., Castro, O., Alvarez, L.D., Dansey, M.V., Escudero, D.S., Veleiro, A.S., Pecci, A., Burton, G., 27-nor-Δ4-dafachronic acid is a synthetic ligand of Caenorhabditis elegans DAF-12 receptor (2013) Bioorg. Med. Chem. Lett., 23, pp. 2893-2896
  • Williams, S., Bledsoe, R.K., Collins, J.L., Boggs, S., Lambert, M.H., Miller, A.B., Moore, J., Willson, T.M., X-ray crystal structure of the liver X receptor beta ligand binding domain: Regulation by a histidine-tryptophan switch (2003) J. Biol. Chem., 278, pp. 27138-27143
  • Dansey, M.V., Alvarez, L.D., Samaja, G., Escudero, D.S., Veleiro, A.S., Pecci, A., Castro, O.A., Burton, G., Synthetic DAF-12 modulators with potential use in controlling nematodes life cycle (2015) Biochem. J., 465, pp. 175-184
  • Theofilopoulos, S., Griffiths, W.J., Crick, P.J., Yang, S., Meljon, A., Ogundare, M., Kitambi, S.S., Wang, Y., Cholestenoic acids regulate motor neuron survival via liver X receptors (2014) J. Clin. Invest., 124, pp. 4829-4842
  • Hu, X., Li, S., Wu, J., Xia, C., Lala, D.S., Liver X receptors interact with corepressors to regulate gene expression (2003) Mol. Endocrinol., 17, pp. 1019-1026
  • Albers, M., Blume, B., Schlueter, T., Wright, M.B., Kober, I., Kremoser, C., Deuschle, U., Koegl, M., A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors (2006) J. Biol. Chem, 281, pp. 4920-4930
  • Son, Y.L., Lee, Y.C., Molecular determinants of the interactions between SRC-1 and LXR/RXR heterodimers (2010) FEBS Lett., 584, pp. 3862-3866
  • Houtman, R., De Leeuw, R., Rondaij, M., Melchers, D., Verwoerd, D., Ruijtenbeek, R., Martens, J.W., Michalides, R., Serine-305 phosphorylation modulates estrogen receptor alpha binding to a coregulator peptide array, with potential application in predicting responses to tamoxifen (2012) Mol. Cancer Ther., 11, pp. 805-816
  • Flaveny, C.A., Griffett, K., El-Gendy, B.E.M., Kazantzis, M., Sengupta, M., Amelio, A.L., Chatterjee, A., Burris, T.P., Broad anti-tumor activity of a small molecule that selectively targets the Warburg effect and lipogenesis (2015) Cancer Cell, 28, pp. 1-15
  • 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, p. 5675
  • Sali, A., Blundell, T.L., Comparative protein modelling by satisfaction of spatial restraints (1993) J. Mol. Biol., 234, p. 779
  • Frisch, M.J., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery, J.A., Jr., Vreven, T., Gaussian Inc., (2004) Wallingford CT
  • Case, D.A., Cheatham, T.E., III, Simmerling, C.L., Wang, J., Duke, R.E., Luo, R., Walker, R.C., Kollman, P.A., (2012) Amber 12
  • Cheatham, T.E., III, Cieplak, P., Kollman, P.A., A modified version of the Cornell et al. Force field with improved sugar pucker phases and helical repeat (1999) J. Biomol. Struct. Dyn., 16, p. 845

Citas:

---------- APA ----------
Álvarez, L.D., Dansey, M.V., Grinman, D.Y., Navalesi, D., Samaja, G.A., Del Fueyo, M.C., Bastiaensen, N.,..., Burton, G. (2015) . Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1851(12), 1577-1586.
http://dx.doi.org/10.1016/j.bbalip.2015.09.007
---------- CHICAGO ----------
Álvarez, L.D., Dansey, M.V., Grinman, D.Y., Navalesi, D., Samaja, G.A., Del Fueyo, M.C., et al. "Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity" . Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids 1851, no. 12 (2015) : 1577-1586.
http://dx.doi.org/10.1016/j.bbalip.2015.09.007
---------- MLA ----------
Álvarez, L.D., Dansey, M.V., Grinman, D.Y., Navalesi, D., Samaja, G.A., Del Fueyo, M.C., et al. "Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity" . Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, vol. 1851, no. 12, 2015, pp. 1577-1586.
http://dx.doi.org/10.1016/j.bbalip.2015.09.007
---------- VANCOUVER ----------
Álvarez, L.D., Dansey, M.V., Grinman, D.Y., Navalesi, D., Samaja, G.A., Del Fueyo, M.C., et al. Destabilization of the torsioned conformation of a ligand side chain inverts the LXRβ activity. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2015;1851(12):1577-1586.
http://dx.doi.org/10.1016/j.bbalip.2015.09.007