PUBLICATION
Homology modeled ligand-binding domains of zebrafish estrogen receptors {alpha}, {beta}1 and {beta}2: from in silico to in vivo studies of estrogen interactions in Danio rerio as a model system
- Authors
- Costache, A.D., Pullela, P.K., Kasha, P., Tomasiewicz, H., and Sem, D.S.
- ID
- ZDB-PUB-050810-7
- Date
- 2005
- Source
- Molecular endocrinology (Baltimore, Md.) 19(12): 2979-2990 (Journal)
- Registered Authors
- Tomasiewicz, Henry
- Keywords
- estrogen receptor, endocrine disruptors, zebrafish, homology model, fluorescence
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Computer Simulation
- Estradiol/analysis
- Estrogen Receptor alpha/chemistry*
- Estrogen Receptor alpha/metabolism
- Estrogen Receptor beta/chemistry
- Estrogen Receptor beta/metabolism
- Estrogens/metabolism*
- Fluorescence
- Germ Cells/chemistry
- Ligands
- Models, Biological
- Molecular Sequence Data
- Protein Conformation
- Sequence Alignment
- Sequence Homology, Amino Acid
- Zebrafish/growth & development
- Zebrafish/metabolism*
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/metabolism
- PubMed
- 16081519 Full text @ Mol. Endocrinol.
Citation
Costache, A.D., Pullela, P.K., Kasha, P., Tomasiewicz, H., and Sem, D.S. (2005) Homology modeled ligand-binding domains of zebrafish estrogen receptors {alpha}, {beta}1 and {beta}2: from in silico to in vivo studies of estrogen interactions in Danio rerio as a model system. Molecular endocrinology (Baltimore, Md.). 19(12):2979-2990.
Abstract
Homology models were constructed for the ligand-binding domains of zebrafish estrogen receptors (zfERs) alpha, beta1 and beta2. Estradiol binding sites are nearly identical between zfERs and their human homologs, suggesting zebrafish will serve as a good model system for studying human ER-binding drugs. Conversely, studies of endocrine disruptor effects on zebrafish will benefit from the wealth of data available on xenoestrogen interactions with human ERs. Compounds flagged by the ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods) for endocrine disruptor screening were docked into our zfER homology models. Ideally, these in silico docking studies would be complemented with in vivo binding studies. To this end, F-E2 (fluorescently-tagged estradiol) was docked into zfERalpha, and found to bind in the same manner as in human ERalpha, with fluorescein preferentially occupying a region between helices 11 and 12. F-E2 was synthesized, and found to localize along the path of primordial germ cell migration in the developing zebrafish embryo at 3 days post fertilization, consistent with previous reports of: (a) a role for estradiol in sex determination, and (b) the first appearance of ERs at 2 days post fertilization. These data provide a foundation for future in silico and in vivo binding studies of estrogen agonists and antagonists with zebrafish ERs.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping