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Allosteric control of ligand selectivity between estrogen receptors alpha and beta: Implications for other nuclear receptors

Academic Article
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Overview

authors

  • Nettles, Kendall
  • Sun, J.
  • Radek, J. T.
  • Sheng, S. B.
  • Rodriguez, A. L.
  • Katzenellenbogen, J. A.
  • Katzenellenbogen, B. S.
  • Greene, G. L.

publication date

  • February 2004

journal

  • Molecular Cell  Journal

abstract

  • Allosteric communication between interacting molecules is fundamental to signal transduction and many other cellular processes. To better understand the relationship between nuclear receptor (NR) ligand positioning and the formation of the coactivator binding pocket, we investigated the determinants of ligand selectivity between the two estrogen receptor subtypes ERalpha and ERbeta. Chimeric receptors and structurally guided amino acid substitutions were used to demonstrate that distinct "hot spot" amino acids are required for ligand selectivity. Residues within the ligand binding pocket as well as distal secondary structural interactions contribute to subtype-specific positioning of the ligand and transcriptional output. Examination of other NRs suggests a mechanism of communication between the ligand and coactivator binding pockets, accounting for partial agonist and dimer-specific activity. These results demonstrate the importance of long-range interactions in the transmission of information through the ligand binding domain as well as in determining the ligand selectivity of closely related NR receptor subtypes.

subject areas

  • Allosteric Regulation
  • Amino Acid Sequence
  • Amino Acids
  • Animals
  • Binding Sites
  • COS Cells
  • Cell Line, Tumor
  • Cell Nucleus
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
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Identity

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/s1097-2765(04)00054-1

PubMed ID

  • 14967140
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Additional Document Info

start page

  • 317

end page

  • 327

volume

  • 13

issue

  • 3

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