Dynamic allosteric communication pathway directing differential activation of the glucocorticoid receptor
Open Access
- 17 July 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (29), eabb5277
- https://doi.org/10.1126/sciadv.abb5277
Abstract
Allosteric communication within proteins is a hallmark of biochemical signaling, but the dynamic transmission pathways remain poorly characterized. We combined NMR spectroscopy and surface plasmon resonance to reveal these pathways and quantify their energetics in the glucocorticoid receptor, a transcriptional regulator controlling development, metabolism, and immune response. Our results delineate a dynamic communication network of residues linking the ligand-binding pocket to the activation function-2 interface, where helix 12, a switch for transcriptional activation, exhibits ligand- and coregulator-dependent dynamics coupled to graded activation. The allosteric free energy responds to variations in ligand structure: subtle changes gradually tune allostery while preserving the transmission pathway, whereas substitution of the entire pharmacophore leads to divergent allosteric control by apparently rewiring the communication network. Our results provide key insights that should aid in the design of mechanistically differentiated ligands.Funding Information
- AstraZeneca
- the Swedish Research Council (621-2014-5815)
This publication has 47 references indexed in Scilit:
- Specific 12CβD212CγD2S13CεHD2 Isotopomer Labeling of Methionine To Characterize Protein Dynamics by 1H and 13C NMR Relaxation DispersionJournal of the American Chemical Society, 2012
- Agonism/antagonism switching in allosteric ensemblesProceedings of the National Academy of Sciences of the United States of America, 2012
- Structural Dynamics, Intrinsic Disorder, and Allostery in Nuclear Receptors as Transcription FactorsJournal of Biological Chemistry, 2011
- Hormone Binding and Co-regulator Binding to the Glucocorticoid Receptor are Allosterically CoupledOnline Journal of Public Health Informatics, 2010
- Molecular Switch in the Glucocorticoid Receptor: Active and Passive Antagonist ConformationsJournal of Molecular Biology, 2010
- Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by DeacylcortivazolMolecular and Cellular Biology, 2008
- A Conformational Switch in the Ligand-binding Domain Regulates the Dependence of the Glucocorticoid Receptor on Hsp90Journal of Molecular Biology, 2007
- Protein production by auto-induction in high-density shaking culturesProtein Expression and Purification, 2005
- LIGAND CONTROL OF COREGULATOR RECRUITMENT TO NUCLEAR RECEPTORSAnnual Review of Physiology, 2005
- A general two-site solution for the chemical exchange produced dependence of T2 upon the carr-Purcell pulse separationJournal of Magnetic Resonance (1969), 1972