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

Sathish Srinivasan, Jerome C. Nwachukwu, Alex A. Parent, Valerie Cavett, Jason Nowak, Travis S. Hughes, Douglas J. Kojetin, John A. Katzenellenbogen, Kendall W. Nettles

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)326-332
Number of pages7
JournalNature Chemical Biology
Volume9
Issue number5
DOIs
StatePublished - May 2013

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