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

Abstract

<div>Glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the</div><div>transcription of specific genes. There is a known allosteric cross-talk between the ligand and coregulator binding</div><div>sites within the GR ligand binding domain that is crucial for the control of the functional response. However, the</div><div>molecular mechanisms underlying such an allosteric control remain elusive. Here, molecular dynamics (MD)</div><div>simulations, bioinformatic analysis and biophysical measurements are integrated to capture the structural and</div><div>dynamic features of the allosteric cross-talk within GR. We identified a network of evolutionarily conserved</div><div>residues that enables the allosteric signal transduction, in agreement with experimental data. MD simulations</div><div>clarify how such network is dynamically interconnected and offer a mechanistic explanation of how the different</div><div>peptides affect the intensity of the allosteric signal. This study provides useful insights to elucidate the GR</div><div>allosteric regulation, ultimately, posing the foundation for designing novel drugs.</div>