Unravelling Allosteric Cross-Talk between Co-Activator Peptide and Ligand Binding Site in Glucocorticoid Receptor

Abstract

Glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the transcription of specific genes. There is a known interconnection between the ligand and co-regulator binding sites of the GR ligand binding domain that is crucial for the functional differentiation of the downstream gene transcription. However, the molecular mechanisms underlying such an allosteric control remain elusive. The integration of molecular dynamics simulations, bioinformatic analysis and biophysical measurements led us to detect a network of dynamically interconnected evolutionary conserved residues that mediates the allosteric signal propagation between the co-regulator docking site and the ligand binding pocket. Co-regulator peptides alter the functionality of this network, explaining why the allosteric response depends on the peptide sequence. These findings provide useful insights for the comprehension of GR allosteric regulation that should help the design of novel drugs.