title: 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.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Nwachukwu
authors.forename: Alex A
authors.initials: AA
authors.lastname: Parent
authors.forename: Valerie
authors.initials: V
authors.lastname: Cavett
authors.forename: Jason
authors.initials: J
authors.lastname: Nowak
authors.forename: Travis S
authors.initials: TS
authors.lastname: Hughes
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
mesh_terms: D000494:Allosteric Regulation; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands