Unraveling the Allosteric Cross-Talk Between Coactivator Peptide and Ligand Binding Site in Glucocorticoid Receptor

Glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the

transcription of specific genes. There is a known allosteric cross-talk between the ligand and coregulator binding

sites within the GR ligand binding domain that is crucial for the control of the functional response. However, the

molecular mechanisms underlying such an allosteric control remain elusive. Here, molecular dynamics (MD)

simulations, bioinformatic analysis and biophysical measurements are integrated to capture the structural and

dynamic features of the allosteric cross-talk within GR. We identified a network of evolutionarily conserved

residues that enables the allosteric signal transduction, in agreement with experimental data. MD simulations

clarify how such network is dynamically interconnected and offer a mechanistic explanation of how the different

peptides affect the intensity of the allosteric signal. This study provides useful insights to elucidate the GR

allosteric regulation, ultimately, posing the foundation for designing novel drugs.

Abstract