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Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition.

Transcriptional regulation by the glucocorticoid receptor (GR) is mediated by hormone binding, receptor dimerization, and coactivator recruitment. Here, we report the crystal structure of the human GR ligand binding domain (LBD) bound to dexamethasone and a coactivator motif derived from the transcriptional intermediary factor 2. Despite structural similarity to other steroid receptors, the GR LBD adopts a surprising dimer configuration involving formation of an intermolecular beta sheet. Functional studies demonstrate that the novel dimer interface is important for GR-mediated activation. The structure also reveals an additional charge clamp that determines the binding selectivity of a coactivator and a distinct ligand binding pocket that explains its selectivity for endogenous steroid hormones. These results establish a framework for understanding the roles of protein-hormone and protein-protein interactions in GR signaling pathways.

Pubmed ID: 12151000


  • Bledsoe RK
  • Montana VG
  • Stanley TB
  • Delves CJ
  • Apolito CJ
  • McKee DD
  • Consler TG
  • Parks DJ
  • Stewart EL
  • Willson TM
  • Lambert MH
  • Moore JT
  • Pearce KH
  • Xu HE



Publication Data

July 12, 2002

Associated Grants


Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Cell Line
  • Crystallization
  • Dexamethasone
  • Dimerization
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Nuclear Receptor Coactivator 2
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Glucocorticoid
  • Recombinant Fusion Proteins
  • Solubility
  • Transcription Factors