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The Caenorhabditis elegans DAF‐12 nuclear receptor: Structure, dynamics, and interaction with ligands
Author(s) -
Alvarez Lautaro D.,
Mañez Pau Arroyo,
Estrin Darío A.,
Burton Gerardo
Publication year - 2012
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24076
Subject(s) - ligand (biochemistry) , molecular dynamics , carboxylate , chemistry , mutant , autodock , caenorhabditis elegans , transactivation , stereochemistry , protein data bank (rcsb pdb) , crystallography , biophysics , receptor , biology , biochemistry , computational chemistry , in silico , transcription factor , gene
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 (25 R )‐Δ 7 ‐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 ce DAF‐12 model was then evaluated by constructing several ligand systems for which the experimental activity is known. Thus, the dynamical behavior of the ce DAF‐12 complex with the more active (25 S )‐Δ 7 ‐DA showed two distinct binding modes, one of them being energetically more favorable compared with the 25 R isomer. Then the effect of the Arg564Cys and Arg598Met mutations on the (25 R )‐Δ 7 ‐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 (25 R )‐Δ 7 ‐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 ce DAF‐12 ligands. Proteins 2012. © 2012 Wiley Periodicals, Inc.