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.

Abstract

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.

Keywords

Glucocorticoid Receptor
Allostery
molecular dynamics
Nuclear Receptors
allosteric signal transmission pathway
evolution
drug discovery
PRGC1
TIF2
dexamethasone

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.