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

05 March 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


Glucocorticoid Receptor
molecular dynamics
Nuclear Receptors
allosteric signal transmission pathway
drug discovery


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