The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands
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 lig...
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todo:paper_08873585_v80_n7_p1798_Alvarez2023-10-03T15:40:53Z The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands Alvarez, L.D. Mañez, P.A. Estrin, D.A. Burton, G. 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 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. Fil:Alvarez, L.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_08873585_v80_n7_p1798_Alvarez |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Alvarez, L.D. Mañez, P.A. Estrin, D.A. Burton, G. The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
Alvarez, L.D. Mañez, P.A. Estrin, D.A. Burton, G. |
| author_facet |
Alvarez, L.D. Mañez, P.A. Estrin, D.A. Burton, G. |
| author_sort |
Alvarez, L.D. |
| title |
The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands |
| title_short |
The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands |
| title_full |
The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands |
| title_fullStr |
The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands |
| title_full_unstemmed |
The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands |
| title_sort |
caenorhabditis elegans daf-12 nuclear receptor: structure, dynamics, and interaction with ligands |
| url |
http://hdl.handle.net/20.500.12110/paper_08873585_v80_n7_p1798_Alvarez |
| work_keys_str_mv |
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