Cited by 46Protein Structure and DynamicsEstrogen and related hormone effectsReceptor Mechanisms and Signaling

Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect of DNA 1 1Edited by P. E. Wright

van Tilborg, M.A.A, Lefstin, J.A, Kruiskamp, M, Teuben, J.-M, Boelens, R, Yamamoto, K.R, Kaptein, R·2000·Journal of Molecular Biology

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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Crossref · 10.1006/jmbi.2000.4001

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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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