Human aryl-hydrocarbon receptor and its interaction with dioxin and physiological ligands investigated by molecular modelling and docking simulations.

Molecular structure of the ligand binding domain of hAhR has been modelled by homology modelling techniques and used for docking simulations with dioxin and nine more xenobiotics and endogenous ligands. The study evidences that different sites may bind these ligands, whereas only one binding site has been previously indicated by past studies on the mouse homologous receptor. The differences in the sequence of mouse and human AhR ligand binding domain may explain this observation, being most of them in the additional sites observed. Preferences of the evaluated ligands for the different sites are reported and discussed in view of their functional role.

[1]  Yanli Wang,et al.  PubChem: Integrated Platform of Small Molecules and Biological Activities , 2008 .

[2]  H. Kikuchi,et al.  Characterization of the region of the aryl hydrocarbon receptor required for ligand dependency of transactivation using chimeric receptor between Drosophila and Mus musculus. , 2009, Biochimica et biophysica acta.

[3]  M. Veldhoen,et al.  External influences on the immune system via activation of the aryl hydrocarbon receptor. , 2011, Seminars in immunology.

[4]  Roy J Vaz,et al.  Identification of optimum computational protocols for modeling the aryl hydrocarbon receptor (AHR) and its interaction with ligands. , 2010, Bioorganic & medicinal chemistry letters.

[5]  A Tramontano,et al.  A model for recognition of polychlorinated dibenzo-p-dioxins by the aryl hydrocarbon receptor. , 2002, European journal of biochemistry.

[6]  A. Chapman-Smith,et al.  The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. , 2004, The international journal of biochemistry & cell biology.

[7]  Y. Fujii‐Kuriyama,et al.  Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli , 2010, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[8]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[9]  M. E. Hahn,et al.  Aryl hydrocarbon receptors: diversity and evolution. , 2002, Chemico-biological interactions.

[10]  H. Edelsbrunner,et al.  Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design , 1998, Protein science : a publication of the Protein Society.

[11]  P. Mandal.  Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology , 2005, Journal of Comparative Physiology B.

[12]  R. Hites.  Dioxins: An Overview and History , 2010 .

[13]  M. Denison,et al.  Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. , 2003, Annual review of pharmacology and toxicology.

[14]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[15]  Y Fujii-Kuriyama,et al.  Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. , 1994, The Journal of biological chemistry.

[16]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[17]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[18]  Christian Cole,et al.  The Jpred 3 secondary structure prediction server , 2008, Nucleic Acids Res..

[19]  Emily A. Stevens,et al.  The aryl hydrocarbon receptor: a perspective on potential roles in the immune system , 2009, Immunology.

[20]  G. Perdew,et al.  Ligand Selectivity and Gene Regulation by the Human Aryl Hydrocarbon Receptor in Transgenic Mice , 2009, Molecular Pharmacology.

[21]  Anna Marabotti,et al.  Theoretical model of the three-dimensional structure of a sugar-binding protein from Pyrococcus horikoshii: structural analysis and sugar-binding simulations. , 2004, The Biochemical journal.

[22]  M. Gough.  Agent Orange: exposure and policy. , 1991, American journal of public health.

[23]  Ruben Abagyan,et al.  Modeling of the aryl hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands. , 2009, Journal of medicinal chemistry.

[24]  G. Perdew,et al.  The aryl hydrocarbon receptor complex and the control of gene expression. , 2008, Critical reviews in eukaryotic gene expression.

[25]  David T. Jones,et al.  pGenTHREADER and pDomTHREADER: new methods for improved protein fold recognition and superfamily discrimination , 2009, Bioinform..

[26]  Christopher A Bradfield,et al.  The search for endogenous activators of the aryl hydrocarbon receptor. , 2008, Chemical research in toxicology.

[27]  Alessandro Pandini,et al.  Detection of the TCDD binding-fingerprint within the Ah receptor ligand binding domain by structurally driven mutagenesis and functional analysis. , 2009, Biochemistry.

[28]  Kevin H. Gardner,et al.  Artificial ligand binding within the HIF2α PAS-B domain of the HIF2 transcription factor , 2009, Proceedings of the National Academy of Sciences.

[29]  Akira Miyamoto,et al.  Identification of amino acid residues in the Ah receptor involved in ligand binding. , 2007, Biochemical and biophysical research communications.

[30]  P. Sassone-Corsi,et al.  Crystal structure and interactions of the PAS repeat region of the Drosophila clock protein PERIOD. , 2005, Molecular cell.

[31]  X. Coumoul,et al.  The aryl hydrocarbon receptor, more than a xenobiotic‐interacting protein , 2007, FEBS letters.

[32]  M. Sippl.  Recognition of errors in three‐dimensional structures of proteins , 1993, Proteins.

[33]  F. Gonzalez,et al.  The aryl hydrocarbon receptor: studies using the AHR-null mice. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[34]  L. Birnbaum,et al.  An Overview of the Effects of Dioxins and Dioxin-Like Compounds on Vertebrates, as Documented in Human and Ecological Epidemiology , 2009, Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews.

[35]  K. Gardner,et al.  Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization. , 2005, Journal of molecular biology.

[36]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[37]  Özkan Yildiz,et al.  Structural and Functional Analyses of PAS Domain Interactions of the Clock Proteins Drosophila PERIOD and Mouse PERIOD2 , 2009, PLoS biology.

[38]  Jian Ye,et al.  BLAST: improvements for better sequence analysis , 2006, Nucleic Acids Res..

[39]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[40]  Alessandro Pandini,et al.  Structural and functional characterization of the aryl hydrocarbon receptor ligand binding domain by homology modeling and mutational analysis. , 2007, Biochemistry.

[41]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[42]  B. Stockinger,et al.  The aryl hydrocarbon receptor in immunity. , 2009, Trends in immunology.

[43]  N. Kerkvliet,et al.  Dioxin and immune regulation , 2010, Annals of the New York Academy of Sciences.

[44]  María Martín,et al.  Ongoing and future developments at the Universal Protein Resource , 2010, Nucleic Acids Res..