Structural determinants of allosteric ligand activation in RXR heterodimers

Cell. 2004 Feb 6;116(3):417-29. doi: 10.1016/s0092-8674(04)00119-9.


Allosteric communication underlies ligand-dependent transcriptional responses mediated by nuclear receptors. While studies have elucidated many of the components involved in this process, the energetic architecture within the receptor protein that mediates allostery remains unknown. Using a sequence-based method designed to detect coevolution of amino acids in a protein, termed the statistical coupling analysis (SCA), we identify a network of energetically coupled residues that link the functional surfaces of nuclear receptor ligand binding domains. Functional analysis of these predicted residues demonstrates their participation in an allosteric network that governs the ability of heterodimeric receptors to activate transcription in response to ligand binding by either partner. Interestingly, mutation of a single network residue can discriminate between receptor activation by endocrine, dietary, and synthetic agonists. These results reveal a structural network required for RXR heterodimer allosteric communication and suggest that the specificity of ligand response and permissivity coevolved to enable signal discrimination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Regulation / physiology
  • Amino Acid Sequence / genetics
  • Binding Sites / genetics
  • Data Interpretation, Statistical
  • Dimerization
  • Evolution, Molecular
  • Humans
  • Ligands
  • Models, Molecular
  • Mutation / genetics
  • Protein Binding / genetics
  • Protein Structure, Tertiary / genetics
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / metabolism
  • Receptors, Retinoic Acid / physiology*
  • Retinoid X Receptors
  • Signal Transduction / genetics
  • Structure-Activity Relationship
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Transcription, Genetic / genetics*


  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factors