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Abstract:

A structure for the ligand binding domain (LBD) of the DAF-12 receptor from Caenorhabditis elegans was obtained from the X-ray crystal structure of the receptor LBD from Strongyloides stercoralis bound to (25R)-Δ7-dafachronic acid (DA) (pdb:3GYU). The model was constructed in the presence of the ligand using a combination of Modeller, Autodock, and molecular dynamics (MD) programs, and then its dynamical behavior was studied by MD. A strong ligand binding mode (LBM) was found, with the three arginines in the ligand binding pocket (LBP) contacting the C-26 carboxylate group of the DA. The quality of the ceDAF-12 model was then evaluated by constructing several ligand systems for which the experimental activity is known. Thus, the dynamical behavior of the ceDAF-12 complex with the more active (25S)-Δ7-DA showed two distinct binding modes, one of them being energetically more favorable compared with the 25R isomer. Then the effect of the Arg564Cys and Arg598Met mutations on the (25R)-Δ7-DA binding was analyzed. The MD simulations showed that in the first case the complex was unstable, consistent with the lack of transactivation activity of (25R)-Δ7-DA in this mutant. Instead, in the case of the Arg598Met mutant, known to produce a partial loss of activity, our model predicted smaller effects on the LBM with a more stable MD trajectory. The model also showed that removal of the C-25 methyl does not impede the simultaneous strong interaction of the carboxylate with the three arginines, predicting that 27-nor-DAs are putative ceDAF-12 ligands. © 2012 Wiley Periodicals, Inc.

Registro:

Documento: Artículo
Título:The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands
Autor:Alvarez, L.D.; Mañez, P.A.; Estrin, D.A.; Burton, G.
Filiación:Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
IFIBYNE (CONICET-UBA), Argentina
Departamento de Química Inorgánica, Analitica y Quimica Física, INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina
Palabras clave:C. elegans; Dafachronic acid; Molecular dynamics; Nuclear receptor, DAF-12; arginine; Caenorhabditis elegans protein; carboxylic acid; cell nucleus receptor; DAF 12 nuclear receptor; unclassified drug; article; binding site; Caenorhabditis elegans; crystal structure; gene mutation; molecular docking; molecular dynamics; molecular model; nonhuman; priority journal; protein analysis; protein interaction; protein structure; Strongyloides stercoralis; transactivation; X ray crystallography; Amino Acid Sequence; Animals; Arginine; Binding Sites; Caenorhabditis elegans Proteins; Cholestenes; Ligands; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Binding; Receptors, Cytoplasmic and Nuclear; Sequence Alignment; Caenorhabditis elegans; Strongyloides stercoralis
Año:2012
Volumen:80
Número:7
Página de inicio:1798
Página de fin:1809
DOI: http://dx.doi.org/10.1002/prot.24076
Título revista:Proteins: Structure, Function and Bioinformatics
Título revista abreviado:Proteins Struct. Funct. Bioinformatics
ISSN:08873585
CAS:arginine, 1119-34-2, 15595-35-4, 7004-12-8, 74-79-3; Arginine, 74-79-3; Caenorhabditis elegans Proteins; Cholestenes; DAF-12 protein, C elegans; Ligands; Receptors, Cytoplasmic and Nuclear; dafachronic acid
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v80_n7_p1798_Alvarez

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Citas:

---------- APA ----------
Alvarez, L.D., Mañez, P.A., Estrin, D.A. & Burton, G. (2012) . The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands. Proteins: Structure, Function and Bioinformatics, 80(7), 1798-1809.
http://dx.doi.org/10.1002/prot.24076
---------- CHICAGO ----------
Alvarez, L.D., Mañez, P.A., Estrin, D.A., Burton, G. "The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands" . Proteins: Structure, Function and Bioinformatics 80, no. 7 (2012) : 1798-1809.
http://dx.doi.org/10.1002/prot.24076
---------- MLA ----------
Alvarez, L.D., Mañez, P.A., Estrin, D.A., Burton, G. "The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands" . Proteins: Structure, Function and Bioinformatics, vol. 80, no. 7, 2012, pp. 1798-1809.
http://dx.doi.org/10.1002/prot.24076
---------- VANCOUVER ----------
Alvarez, L.D., Mañez, P.A., Estrin, D.A., Burton, G. The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands. Proteins Struct. Funct. Bioinformatics. 2012;80(7):1798-1809.
http://dx.doi.org/10.1002/prot.24076