期刊
MOLECULAR SYSTEMS BIOLOGY
卷 12, 期 4, 页码 -出版社
WILEY
DOI: 10.15252/msb.20156701
关键词
Breast cancer; Chemical biology; Crystal structure; Nuclear receptor; Signal transduction
资金
- National Institutes of Health [PHS 5R37DK015556, 5R33CA132022, 5R01DK077085]
- Frenchman's Creek Women for Cancer Research
- BallenIsles Men's Golf Association
- NSFC [81573279, 81172935, 81373255]
- Key Project of Ministry of Education [313040]
- Open Research Fund Program of the State Key Laboratory of Virology of China [2011002]
- National Science Foundation [1359369]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [1359369] Funding Source: National Science Foundation
Some estrogen receptor-alpha (ER alpha)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ER alpha ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ER alpha activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter-atomic distance in the ligand-binding domain predicted their proliferative effects. In contrast, the N-terminal coactivator-binding site, activation function-1 (AF-1), determined cell-specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ER alpha.
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