Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns.
Because of the concern about environmental chemicals with oestrogenic and anti-oestrogenic effects, there is a need to construct biosensors for classifying such chemicals according to their effect on oestrogen receptor conformation. The conformation of the ligand-binding domains (LBD) of oestrogen receptor-alpha and -beta determine their transcription regulation activity. Some ligands, i.e., the natural oestrogen oestradiol, induce an active conformation allowing interaction with co-activators. In contrast, antagonists like ICI 182, 780, because of their bulky side chains, do not allow an alpha-helix 12 positioning compatible with co-activator binding. Another type of oestrogen receptor-ligand interactions, termed "passive antagonism", was first defined by X-ray crystal structure analysis of receptors in complex with the side chain-less 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC). We have now used the ability of peptides selected from phage-displayed peptide libraries to bind conformation specifically to oestrogen receptor-alpha and -beta LBDs to analyse conformations induced by THC and a group of chlorinated biphenyls and their aryl-hydroxylated metabolites, suspected of being environmental chemical disruptors. In oestrogen receptor-beta, THC defined a "passive antagonist" peptide recognition pattern, which was also induced by several antagonistic hydroxylated biphenyls, while a clearly different peptide recognition pattern was induced by their chlorinated agonistic counterparts. In oestrogen receptor-alpha, THC induced a conformation similar to that induced by oestriol and other oestrogen receptor-alpha agonists, which, as evaluated by site-directed mutagenesis, have a functionally important interaction with oestrogen receptor-alpha residue His524. We conclude that the peptide recognition pattern can be used to classify suspected environmental endocrine disruptors according the oestrogen receptor-alpha and -beta conformations they induce.
Sumbayev
Vadim V
VV
Department of Molecular Biology, University of Aarhus, Denmark.
Jensen
Jan K
JK
Hansen
Jacob A
JA
Andreasen
Peter A
PA
D001435:Bacteriophages; D004797:Enzyme-Linked Immunosorbent Assay; D007700:Kinetics; D008024:Ligands; D050505:Mutant Proteins / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020349:Surface Plasmon Resonance
D008024:Ligands; D050505:Mutant Proteins; D010455:Peptides; D011960:Receptors, Estrogen; D011078:Polychlorinated Biphenyls