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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Detalles Bibliográficos
Autores principales: Alvarez, Lautaro Damián, Estrin, Dario Ariel, Burton, Gerardo
Publicado: 2012
Materias:
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
Acceso en línea:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v80_n7_p1798_Alvarez
http://hdl.handle.net/20.500.12110/paper_08873585_v80_n7_p1798_Alvarez
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario: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.

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