A dynamic structural model for estrogen receptor-alpha activation by ligands, emphasizing the role of interactions between distant A and E domains

Mol Cell. 2002 Nov;10(5):1019-32. doi: 10.1016/s1097-2765(02)00746-3.


The functional interplay between different domains of estrogen receptor-alpha (ERalpha, NR3A1) is responsible for the overall properties of the full-length protein. We previously identified an interaction between the N-terminal A and C-terminal domains, which we demonstrate here to repress ligand-independent transactivation and transrepression abilities of ERalpha. Using targeted mutations based on ERalpha structural models, we determine the basis for this interaction that defines a regulatory interplay between ERalpha A domain, corepressors, and ERalpha Helix 12 for binding to the same C-terminal surface. We propose a dynamic model where binding of different ligands influences the A/D-F domain interaction and results in specific functional outcomes. This model gives insights into the dynamic properties of full-length ERalpha and into the structure of unliganded ERalpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Estrogen Receptor alpha
  • Gene Silencing
  • Genes, Reporter
  • Glutathione Transferase / metabolism
  • HeLa Cells
  • Humans
  • Ligands
  • Models, Genetic
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Peptides / chemistry
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Biosynthesis
  • Protein Conformation
  • Protein Isoforms
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Software
  • Transcription, Genetic
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • beta-Galactosidase / metabolism


  • Estrogen Receptor alpha
  • Ligands
  • Peptides
  • Protein Isoforms
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Glutathione Transferase
  • beta-Galactosidase