title: Homology-modeled ligand-binding domains of medaka estrogen receptors and androgen receptors: a model system for the study of reproduction.
abstract: Estrogen and androgen and their receptors play critical roles in physiological processes such as sexual differentiation and development. Using the available structural models for the human estrogen receptors alpha and beta and androgen receptor as templates, we designed in silico agonist and antagonist models of medaka estrogen receptor (meER) alpha, beta-1, and beta-2, and androgen receptor (meAR) alpha and beta. Using these models, we studied (1) the structural relationship between the ligand-binding domains (LBDs) of ERs and ARs of human and medaka, and (2) whether medaka ER and AR can be potential models for studying the ligand-binding activities of various agonists and antagonists of these receptors by docking analysis. A high level of conservation was observed between the sequences of the ligand-binding domains of meERalpha and huERalpha, meERbeta1 and huERbeta, meERbeta2, and huERbeta with 62.8%, 66.4%, and 65.1% identity, respectively. The sequence conservation between meARalpha and huAR, meARbeta, and huAR was found with 70.1% and 61.0% of identity, respectively. Thirty-three selected endocrine disrupting chemicals (EDCs), including both agonists and antagonists, were docked into the LBD of ER and AR, and the corresponding docking score for medaka models and human templates were calculated. In order to confirm the conservation of the overall geometry and the binding pocket, the backbone root mean square deviation (RMSD) for Calpha atoms was derived from the structure superposition of all 10 medaka homology models to the six human templates. Our results suggested conformational conservation between the ERs and ARs of medaka and human, Thus, medaka could be highly useful as a model system for studies involving estrogen and androgen interaction with their receptors.
authors.affiliation: Laboratory of Reproductive Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan. jzcui@umd.edu
authors.forename: Jianzhou
authors.initials: J
authors.lastname: Cui
authors.forename: Xueyan
authors.initials: X
authors.lastname: Shen
authors.forename: Zuowei
authors.initials: Z
authors.lastname: Yan
authors.forename: Haobin
authors.initials: H
authors.lastname: Zhao
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagahama
mesh_terms: D000595:Amino Acid Sequence; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D047628:Estrogen Receptor alpha; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009990:Oryzias / Q000378:metabolism / Q000502:physiology*; D011944:Receptors, Androgen / Q000502:physiology*; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012098:Reproduction / Q000502:physiology*
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; C442419:estrogen receptor alpha, medaka