The Aryl hydrocarbon Receptor (AhR) is a ligand dependent intracellular receptor that can stimulate gene transcription in response to xenobiotics, in a wide range of species. The ability of the AhR to bind and be activated by a number of structurally divergent chemicals (synthetic, environmental, naturally occurring dietary and endogenous ligands) suggests that the AhR contains a rather promiscuous ligand binding site.1 The investigation of the possible ligand-activated mechanism of the AhR has been one of the research topics of our group since several years. As the three-dimensional structure of the AhR has not been solved so far, apo homology models for the PAS B domain of AhRs of different species were developed and characterized in our group, and they were validated by experimental mutagenesis and functional analysis.2,3 Recently, some crystallographic complexes of the HIF2α protein, one of the templates used for the modelling, were deposited in the PDB.4 Starting from these new structural data, the homology models of the mouse and rat AhR (mAhR, rtAhR) PAS B domains have been reviewed and updated. The inclusion of the templates ligands during the homology modelling has allowed to obtain a “ligand induced fit” binding cavity, which appeared wider than in the previous model. Moreover, an accurate structural analysis of the residues defining the binding site has highlighted a certain conformational flexibility that affects the cavity dimension. Considering that the problem of the protein conformational heterogeneity is particularly difficult to manage in virtual screening,5 a few representative conformations have been selected by cluster analysis and then used as targets for a cross docking approach. A medium-sized set of 142 ligands, for which the experimental activities (KD) on the rtAhR are known, was cross docked in the selected rtAhR/PAS B representative models. An accurate analysis of the obtained docking results is ongoing and different approaches for the post-docking refinement of the ligands poses and scores are under evaluation. Correlations of the binding site Molecular Interaction Fields and docking results will be carried out too.
Motto, I., Bonati, L. (2010). Modelling ligands/Aryl hydrocarbon Receptor binding interactions. Intervento presentato a: From Molecular Structure to Systems Biology - Congresso nazionale 2010 della Divisione di Chimica dei Sistemi Biologici, San Vito di Cadore.
Modelling ligands/Aryl hydrocarbon Receptor binding interactions
MOTTO, ILARIA;BONATI, LAURA
2010
Abstract
The Aryl hydrocarbon Receptor (AhR) is a ligand dependent intracellular receptor that can stimulate gene transcription in response to xenobiotics, in a wide range of species. The ability of the AhR to bind and be activated by a number of structurally divergent chemicals (synthetic, environmental, naturally occurring dietary and endogenous ligands) suggests that the AhR contains a rather promiscuous ligand binding site.1 The investigation of the possible ligand-activated mechanism of the AhR has been one of the research topics of our group since several years. As the three-dimensional structure of the AhR has not been solved so far, apo homology models for the PAS B domain of AhRs of different species were developed and characterized in our group, and they were validated by experimental mutagenesis and functional analysis.2,3 Recently, some crystallographic complexes of the HIF2α protein, one of the templates used for the modelling, were deposited in the PDB.4 Starting from these new structural data, the homology models of the mouse and rat AhR (mAhR, rtAhR) PAS B domains have been reviewed and updated. The inclusion of the templates ligands during the homology modelling has allowed to obtain a “ligand induced fit” binding cavity, which appeared wider than in the previous model. Moreover, an accurate structural analysis of the residues defining the binding site has highlighted a certain conformational flexibility that affects the cavity dimension. Considering that the problem of the protein conformational heterogeneity is particularly difficult to manage in virtual screening,5 a few representative conformations have been selected by cluster analysis and then used as targets for a cross docking approach. A medium-sized set of 142 ligands, for which the experimental activities (KD) on the rtAhR are known, was cross docked in the selected rtAhR/PAS B representative models. An accurate analysis of the obtained docking results is ongoing and different approaches for the post-docking refinement of the ligands poses and scores are under evaluation. Correlations of the binding site Molecular Interaction Fields and docking results will be carried out too.
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