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Different positioning of the ligand‐binding domain helix 12 and the F domain of the estrogen receptor accounts for functional differences between agonists and antagonists
Author(s) -
Nichols Mark,
Rientjes Jeanette M.J.,
Stewart A. Francis
Publication year - 1998
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/17.3.765
Subject(s) - biology , estrogen receptor , domain (mathematical analysis) , receptor , helix (gastropod) , microbiology and biotechnology , estrogen , ligand (biochemistry) , computational biology , genetics , ecology , cancer , breast cancer , snail , mathematical analysis , mathematics
The estrogen receptor is capable of binding a diverse set of ligands that are broadly categorized as agonists or antagonists, depending on their abilities to induce or interfere with transcriptional responsiveness. We show, using a fusion protein assay for ligand‐binding which does not rely on transcriptional responsiveness, that agonists and antagonists differently position the C‐terminus of the ligand‐binding domain (helix 12) and the F domain. Upon antagonist binding, the F domain interferes with the fusion protein activity. Mutational disruption of helix 12 alters the position of the F domain, imposing interference after agonist or antagonist binding. Genetically selected inversion mutations where only agonists, but not antagonists, induce interference are similarly reliant on helix 12 and F domain positioning. Our results demonstrate that agonists and antagonists differently position helix 12 and implicate the F domain in mechanisms of antagonist action.