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A novel pesticide‐induced conformational state of the oestrogen receptor ligand‐binding domain, detected by conformation‐specific peptide binding
Author(s) -
Sumbayev Vadim V.,
Bonefeld-Jørgensen Eva C.,
Wind Troels,
Andreasen Peter A.
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.12.025
Subject(s) - receptor , peptide , chemistry , transactivation , ligand (biochemistry) , tamoxifen , nuclear receptor , binding site , stereochemistry , biochemistry , transcription factor , medicine , gene , cancer , breast cancer
The diverse effects of different natural and synthetic oestrogen receptor ligands depend on induction of different receptor conformations, allowing differential interactions with other transcription factors. Different conformations of the oestrogen receptor ligand binding domains can be monitored by conformation‐specific binding to peptides selected from phage‐displayed peptide libraries. We now report that a group of chlorinated pesticides, including 2,4‐dichlorodiphenyl‐dichloroethylene, induces a peptide recognition pattern different from those induced by any one of the classical oestrogen receptor ligands. The pesticide‐complexed oestrogen receptors recognized peptides reacting with the receptors complexed both with the natural oestrogen 17β‐oestradiol and with the synthetic partial antagonist 4‐hydroxy‐tamoxifen, respectively, indicating that the pesticide‐induced conformation shares features with both the 17β‐oestradiol‐ and the 4‐hydroxy‐tamoxifen‐induced conformations. The substitution H524A in the ligand binding domain conferred the pesticide‐specific peptide recognition pattern and transactivation activity to the oestradiol‐ and the 4‐hydroxy‐tamoxifen‐complexed receptors, indicating that one important determinant of the pesticide‐induced conformation is a lack of stabilisation of any one particular receptor conformation by ligand interaction with H524, which is known to interact with both oestradiol and 4‐hydroxy‐tamoxifen. Thus, peptide binding analyses of oestrogen receptor conformations induced by environmental endocrine disruptors can give novel information about molecular mechanisms of oestrogen action in general.