Probing the topological tolerance of multimeric protein interactions: evaluation of an estrogen/synthetic ligand for FK506 binding protein conjugate

Bioconjug Chem. 2010 Oct 20;21(10):1880-9. doi: 10.1021/bc100266v.


Bivalent small molecules composed of a targeting element and an element that recruits endogenous proteins have been shown to block protein-protein interactions in some systems. We have attempted to apply such an approach to disrupt the interaction of the estrogen receptor α with either its associated coactivators or its dimerization partner (i.e., another estrogen receptor). We show here that a conjugate capable of simultaneously binding both the estrogen receptor and a recruited protein (FK506 Binding Protein 12 kDa) is, however, incapable of disrupting the multimeric estrogen receptor dimer/coactivator complex both in vitro and in cell-based reporter gene assays. We postulate why it may not be possible to disrupt this particular protein-protein complex-as well as other systems having high topological tolerance-with such bivalent inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Down-Regulation
  • Drug Design
  • Estradiol / metabolism
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Genes, Reporter / genetics
  • Humans
  • Ligands
  • Nuclear Receptor Coactivator 3 / chemistry
  • Nuclear Receptor Coactivator 3 / metabolism
  • Protein Multimerization*
  • Protein Structure, Quaternary
  • Tacrolimus Binding Protein 1A / metabolism
  • Tacrolimus Binding Proteins / chemistry*
  • Tacrolimus Binding Proteins / metabolism*


  • Estrogen Receptor alpha
  • Estrogens
  • Ligands
  • Estradiol
  • Nuclear Receptor Coactivator 3
  • Tacrolimus Binding Protein 1A
  • Tacrolimus Binding Proteins