Mutations in the glucocorticoid receptor DNA-binding domain mimic an allosteric effect of DNA

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...

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Bibliographic Details
Published in:Journal of molecular biology 2000-08, Vol.301 (4), p.947-958
Main Authors: van Tilborg, M A, Lefstin, J A, Kruiskamp, M, Teuben, J, Boelens, R, Yamamoto, K R, Kaptein, R
Format: Article
Language:English
Subjects:
Allosteric Regulation
Allosteric Site
Amino Acid Sequence
Amino Acid Substitution
Animals
Cysteine - genetics
Cysteine - metabolism
Dimerization
DNA - chemistry
DNA - genetics
DNA - metabolism
Models, Molecular
Molecular Sequence Data
Mutation
Nuclear Magnetic Resonance, Biomolecular
Nucleic Acid Conformation
Protein Binding
Protein Conformation
Receptors, Glucocorticoid - chemistry
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - metabolism
Response Elements - genetics
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Summary: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.
ISSN:0022-2836
DOI:10.1006/jmbi.2000.4001