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

Academic Article
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Overview

authors

  • Srinivasan, S.
  • Nwachukwu, J. C.
  • Parent, A. A.
  • Cavett, V.
  • Nowak, J.
  • Hughes, T. S.
  • Kojetin, Douglas
  • Katzenellenbogen, J. A.
  • Nettles, Kendall

publication date

  • May 2013

journal

  • Nature Chemical Biology  Journal

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.

subject areas

  • Allosteric Regulation
  • Cell Proliferation
  • Estrogen Receptor alpha
  • HEK293 Cells
  • Humans
  • Ligands
  • MCF-7 Cells
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Signal Transduction
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Identity

PubMed Central ID

  • PMC3631275

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.1214

PubMed ID

  • 23524984
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Additional Document Info

start page

  • 326

end page

  • 332

volume

  • 9

issue

  • 5

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