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Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α

Abstract

Ligand-binding dynamics control allosteric signaling through the estrogen receptor-α (ERα), 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 ERα-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 ERα-mediated signaling.

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Figure 1: ERα structure and ligand sets.
Figure 2: Structural validation of ligand binding.
Figure 3: Ligand phenotyping.
Figure 4: Cellular correlates of ER proliferation.
Figure 5: Identification of dynamic ligands based on DBD profile.
Figure 6: DBD-activity profile predicts signaling outcomes.

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Acknowledgements

We thank J.L. Cleveland for critically evaluating the manuscript. This research was supported by the US National Institutes of Health (PHS 5R37 DK015556 to J.A.K.; 5R33CA132022 and 5R01DK077085 to K.W.N.). S.S. is supported by the Frenchman's Creek Women for Cancer Research.

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S.S. and J.C.N. designed and performed experiments and wrote the manuscript; A.A.P., V.C., J.N. and T.S.H. performed experiments; D.J.K. designed experiments; and J.A.K. and K.W.N. designed experiments and wrote the manuscript.

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Correspondence to Kendall W Nettles.

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The authors declare no competing financial interests.

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Srinivasan, S., Nwachukwu, J., Parent, A. et al. Ligand-binding dynamics rewire cellular signaling via estrogen receptor-α. Nat Chem Biol 9, 326–332 (2013). https://doi.org/10.1038/nchembio.1214

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