Unraveling the Allosteric Cross-Talk between the Coactivator Peptide and the Ligand-Binding Site in the Glucocorticoid Receptor
| Autor: | Anders Gunnarsson, Anders Hogner, Giuseppina La Sala, Andrey I. Frolov, Christian Tyrchan, Karl Edman |
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| Rok vydání: | 2021 |
| Předmět: |
General Chemical Engineering
Allosteric regulation Computational biology Library and Information Sciences Ligands 01 natural sciences Receptors Glucocorticoid Glucocorticoid receptor Allosteric Regulation Transcription (biology) 0103 physical sciences Coactivator Humans Binding site Binding Sites 010304 chemical physics Chemistry General Chemistry Ligand (biochemistry) 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry Nuclear receptor Signal transduction Peptides Allosteric Site Protein Binding |
| Zdroj: | Journal of Chemical Information and Modeling. 61:3667-3680 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.1c00323 |
| Popis: | The 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 the 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 a network is dynamically interconnected and offer a mechanistic explanation of how different peptides affect the intensity of the allosteric signal. This study provides useful insights to elucidate the GR allosteric regulation, ultimately providing a foundation for designing novel drugs. |
| Databáze: | OpenAIRE |
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