Journal
NATURE CHEMICAL BIOLOGY
Volume 9, Issue 5, Pages 326-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1214
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Funding
- US National Institutes of Health [PHS 5R37 DK015556, 5R33CA132022, 5R01DK077085]
- Frenchman's Creek Women for Cancer Research
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Ligand-binding dynamics control allosteric signaling through the estrogen receptor-alpha (ER alpha), but the biological consequences of such dynamic binding orientations are unknown. Here, we compare a set of ER ligands having dynamic binding orientation (dynamic ligands) with a control set of isomers that are constrained to bind in a single orientation (constrained ligands). Proliferation of breast cancer cells directed by constrained ligands is associated with DNA binding, coactivator recruitment and activation of the estrogen-induced gene GREB1, reflecting a highly interconnected signaling network. In contrast, proliferation driven by dynamic ligands is associated with induction of ER alpha-mediated transcription in a DNA-binding domain (DBD)-dependent manner. Further, dynamic ligands showed enhanced anti-inflammatory activity. The DBD-dependent profile was predictive of these signaling patterns in a larger diverse set of natural and synthetic ligands. Thus, ligand dynamics directs unique signaling pathways and reveals a new role of the DBD in allosteric control of ER alpha-mediated signaling.
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