Rewiring Ancient Residue Interaction Networks Drove the Evolution of Specificity in Steroid Receptors

Structure. 2020 Feb 4;28(2):196-205.e3. doi: 10.1016/j.str.2019.11.012. Epub 2019 Dec 9.


Understanding how changes in amino acid sequence alter protein dynamics and allosteric signaling would illuminate strategies for protein design. To gain insight into this process, we have combined molecular dynamics simulations with ancestral sequence reconstruction to explore conformational dynamics in two ancient steroid receptors (SRs) to determine how allosteric signaling pathways were altered over evolution to generate hormone specificity. In a broad panel of aromatized and non-aromatized hormones, we investigate inter-residue contacts that facilitate allosteric signaling. This work reveals interhelical interactions that act as ligand sensors and explain the structural and dynamical basis for ligand discrimination in SRs. These sensors are part of a conserved SR allosteric network and persist over long simulation time scales, indicating that evolutionary substitutions rewire ancient SR networks to achieve functional evolution. This powerful combination of computation, ancestral reconstruction, and biochemistry may illuminate allosteric mechanisms and functional evolution in other protein families.

Keywords: allostery; ancestral sequence reconstruction; functional evolution; molecular dynamics simulations; protein dynamics; residue interaction networks; steroid receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Evolution, Molecular
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Mutation
  • Phylogeny
  • Protein Conformation
  • Protein Structure, Secondary
  • Receptors, Steroid / chemistry*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism*
  • Signal Transduction


  • Ligands
  • Receptors, Steroid