Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns

Sumbayev, Vadim V. and Jensen, Jan K. and Hansen, Jacob A. and Andreasen, Peter A. (2008) Novel modes of oestrogen receptor agonism and antagonism by hydroxylated and chlorinated biphenyls, revealed by conformation-specific peptide recognition patterns. Molecular and Cellular Endocrinology, 287 (1-2). pp. 30-39. ISSN 0303-7207. (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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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-P, 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-a 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.

Item Type: Article
Uncontrolled keywords: endocrine disruptors; phage display; nuclear receptors; oestrogen; biphenyls
Subjects: Q Science > QP Physiology (Living systems) > QP517 Biochemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Faculties > Science Technology and Medical Studies > Medway School of Pharmacy
Depositing User: Louise Dorman
Date Deposited: 20 May 2009 13:16
Last Modified: 06 Jun 2014 08:55
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