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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Autor principal: Alvarez, L.D
Otros Autores: Mañez, P.A, Estrin, D.A, Burton, G.
Formato: Capítulo de libro
Lenguaje:Inglés
Publicado: 2012
Acceso en línea:Registro en Scopus
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Registro en la Biblioteca Digital
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024 7 |2 scopus  |a 2-s2.0-84862193963 
024 7 |2 cas  |a 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 
040 |a Scopus  |b spa  |c AR-BaUEN  |d AR-BaUEN 
100 1 |a Alvarez, L.D. 
245 1 4 |a The Caenorhabditis elegans DAF-12 nuclear receptor: Structure, dynamics, and interaction with ligands 
260 |c 2012 
270 1 0 |m Burton, G.; Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Pabellón 2, C1428EGA Ciudad de Buenos Aires, Argentina; email: burton@qo.fcen.uba.ar 
506 |2 openaire  |e Política editorial 
504 |a Kaletta, T., Hengartner, M.O., Finding function in novel targets: C. elegans as a model organism (2006) Nat Rev Drug Discov, 5, pp. 387-398 
504 |a Motola, D.L., Cummins, C.L., Rottiers, V., Sharma, K.K., Li, T., Li, Y., Suino-Powell, K., Mangelsdorf, D.J., Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans (2006) Cell, 124, pp. 1209-1223 
504 |a Beckstead, R.B., Thummel, C.S., Indicted: worms caught using steroids (2006) Cell, 124, pp. 1137-1140 
504 |a Hochbaum, D., Zhang, Y., Stuckenholz, C., Labhart, P., Alexiadis, V., Martin, R., Knölker, H.J., Fisher, A.L., DAF-12 regulates a connected network of genes to ensure robust developmental decisions (2011) PLoS Genet, 7, pp. e1002179 
504 |a Antebi, A., Yeh, W.H., Tait, D., Hedgecock, E.M., Riddle, D.L., daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans (2000) Genes Dev, 14, pp. 1512-1527 
504 |a Gerisch, B., Weitzel, C., Kober-Eisermann, C., Rottiers, V., Antebi, A., A hormonal signaling pathway influencing C. elegans metabolism, reproductive development, and life span (2001) Dev Cell, 1, pp. 841-851 
504 |a Wang, Z., Zhou, X.E., Motola, D.L., Gao, X., Suino-Powell, K., Conneely, A., Ogata, C., Mangelsdorf, D.J., Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes (2009) Proc Natl Acad Sci USA, 106, pp. 9138-9143 
504 |a Martin, R., Entchev, E.V., Däbritz, F., Kurzchalia, T.V., Knölker, H.J., Synthesis and hormonal activity of the (25S)-cholesten-26-oic acids-potent ligands for the DAF-12 receptor in Caenorhabditis elegans (2009) Eur J Org Chem, pp. 3703-3714 
504 |a Sharma, K.K., Wang, Z., Motola, D.L., Cummins, C.L., Mangelsdorf, D.J., Auchus, R.J., Synthesis and activity of dafachronic acid ligands for the C. elegans DAF-12 nuclear hormone receptor (2009) Mol Endocrinol, 23, pp. 640-648 
504 |a Martin, R., Entchev, E.V., Kurzchalia, T.V., Knölker, H.J., Steroid hormones controlling the life cycle of the nematode Caenorhabditis elegans: stereoselective synthesis and biology (2010) Org Biomol Chem, 8, pp. 739-750 
504 |a Sali, A., Blundell, T.L., Comparative protein modelling by satisfaction of spatial restraints (1993) J Mol Biol, 234, pp. 779-815 
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504 |a Case, D.A., Darden, T.A., Cheatham III, T.E., Simmerling, C.L., Wang, J., Duke, R.E., Luo, R., Kollman, P.A., (2010) Amber, Version 11, , San Francisco: University of California 
504 |a Weichenberger, C.X., Sippl, M.J., NQ-Flipper: recognition and correction of erroneous asparagine and glutamine side-chain rotamers in protein structures (2007) Nucleic Acids Res, 35, pp. W403-W406. , Web Server Issue 
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520 3 |a 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.  |l eng 
593 |a Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina 
593 |a IFIBYNE (CONICET-UBA), Argentina 
593 |a Departamento de Química Inorgánica, Analitica y Quimica Física, INQUIMAE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina 
690 1 0 |a C. ELEGANS 
690 1 0 |a DAFACHRONIC ACID 
690 1 0 |a MOLECULAR DYNAMICS 
690 1 0 |a NUCLEAR RECEPTOR, DAF-12 
690 1 0 |a ARGININE 
690 1 0 |a CAENORHABDITIS ELEGANS PROTEIN 
690 1 0 |a CARBOXYLIC ACID 
690 1 0 |a CELL NUCLEUS RECEPTOR 
690 1 0 |a DAF 12 NUCLEAR RECEPTOR 
690 1 0 |a UNCLASSIFIED DRUG 
690 1 0 |a ARTICLE 
690 1 0 |a BINDING SITE 
690 1 0 |a CAENORHABDITIS ELEGANS 
690 1 0 |a CRYSTAL STRUCTURE 
690 1 0 |a GENE MUTATION 
690 1 0 |a MOLECULAR DOCKING 
690 1 0 |a MOLECULAR DYNAMICS 
690 1 0 |a MOLECULAR MODEL 
690 1 0 |a NONHUMAN 
690 1 0 |a PRIORITY JOURNAL 
690 1 0 |a PROTEIN ANALYSIS 
690 1 0 |a PROTEIN INTERACTION 
690 1 0 |a PROTEIN STRUCTURE 
690 1 0 |a STRONGYLOIDES STERCORALIS 
690 1 0 |a TRANSACTIVATION 
690 1 0 |a X RAY CRYSTALLOGRAPHY 
690 1 0 |a AMINO ACID SEQUENCE 
690 1 0 |a ANIMALS 
690 1 0 |a ARGININE 
690 1 0 |a BINDING SITES 
690 1 0 |a CAENORHABDITIS ELEGANS PROTEINS 
690 1 0 |a CHOLESTENES 
690 1 0 |a LIGANDS 
690 1 0 |a MOLECULAR DYNAMICS SIMULATION 
690 1 0 |a MOLECULAR SEQUENCE DATA 
690 1 0 |a PROTEIN BINDING 
690 1 0 |a RECEPTORS, CYTOPLASMIC AND NUCLEAR 
690 1 0 |a SEQUENCE ALIGNMENT 
690 1 0 |a CAENORHABDITIS ELEGANS 
690 1 0 |a STRONGYLOIDES STERCORALIS 
700 1 |a Mañez, P.A. 
700 1 |a Estrin, D.A. 
700 1 |a Burton, G. 
773 0 |d 2012  |g v. 80  |h pp. 1798-1809  |k n. 7  |p Proteins Struct. Funct. Bioinformatics  |x 08873585  |t Proteins: Structure, Function and Bioinformatics 
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856 4 0 |u https://doi.org/10.1002/prot.24076  |y DOI 
856 4 0 |u https://hdl.handle.net/20.500.12110/paper_08873585_v80_n7_p1798_Alvarez  |y Handle 
856 4 0 |u https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08873585_v80_n7_p1798_Alvarez  |y Registro en la Biblioteca Digital 
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999 |c 70493