Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect of DNA 1 1Edited by P. E. Wright
Abstract
Two previously isolated mutations in the glucocorticoid receptor DNA-binding domain (DBD), S459A and P493R, have been postulated to mimic DNA-induced conformational changes in the glucocorticoid receptor DBD, thereby constitutively triggering an allosteric mechanism in which binding of specific DNA normally induces the exposure of otherwise silent glucocorticoid receptor transcriptional activation surfaces. Here we report the three-dimensional structure of the free S459A and P493R mutant DBDs as determined by NMR spectroscopy. The free S459A and P493R structures both display the conformational changes in the DBD dimerization interface that are characteristic of the DNA-bound wild-type DBD, confirming that these mutations mimic an allosteric effect of DNA. A transition between two packing arrangements of the DBD hydrophobic core provides a mechanism for long-range transmission of conformational changes, induced either by the mutations or by DNA binding, to protein-protein contact surfaces.
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Changes as subtle as the permutation of a single base pair in GREs modify the conformation of the liganded GR.
“Lastly, genome wide analyses unraveled that changes as subtle as the permutation of a single bp in GREs modifies the conformation of the liganded GR.”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [126]
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- Authors
- van Tilborg, M. A. A., Lefstin, J. A., Kruiskamp, M., Teuben, J.-M., Boelens, R., Yamamoto, K. R., & Kaptein, R.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Kaptein, R
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2000-08
- Volume
- 301
- Issue
- 4
- Pages
- 947-958
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2043644194
- Cited by
- 46
- References
- 44
- Citations by year
- 2024: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2016: 2 · 2014: 2 · 2013: 2 · 2012: 5
- Type
- book review
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Foundation for the National Institutes of Health
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- glucocorticoid receptor, DNA-binding domain, allosteric regulation, receptor dimerization, hydrophobic core packing, transcriptional activation, NMR structure
- MeSH terms
- Allosteric Regulation, Allosteric Site, Amino Acid Sequence, Animals, Cysteine, DNA, Models, Molecular, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, Protein Binding, Protein Conformation, Receptors, Glucocorticoid, Dimerization, Nuclear Magnetic Resonance, Biomolecular, Amino Acid Substitution, Response Elements
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