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 thetranscription of specific genes. There is a known allosteric cross-talk between the ligand and coregulator bindingsites within the GR ligand binding domain that is crucial for the control of the functional response. However, themolecular mechanisms underlying such an allosteric control remain elusive. Here, molecular dynamics (MD)simulations, bioinformatic analysis and biophysical measurements are integrated to capture the structural anddynamic features of the allosteric cross-talk within GR. We identified a network of evolutionarily conservedresidues that enables the allosteric signal transduction, in agreement with experimental data. MD simulationsclarify how such network is dynamically interconnected and offer a mechanistic explanation of how the differentpeptides affect the intensity of the allosteric signal. This study provides useful insights to elucidate the GRallosteric regulation, ultimately, posing the foundation for designing novel drugs.