BIOMAT Database Logo BIOMAT Database Logo

Structure and dynamics of the glucocorticoid receptor DNA-binding domain: comparison of wild type and a mutant with altered specificity. 1997

H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
Center for Structural Biochemistry, Royal Institute of Technology and Karolinska Institute, Novum, S-141 57 Huddinge, Sweden.

Nuclear magnetic resonance was used to compare parameters reflecting solution structure and dynamics of the glucocorticoid receptor DNA-binding domain (GRDBD), which binds specifically to a GRE binding site on DNA, and a triple mutant (GRDBDEGA), which binds to an ERE site. The studies were prompted by an earlier observation that the cooperativity for dimeric DNA-binding is 10 times higher for the GRDBDEGA-ERE association than for the GRDBD-GRE association (Lundbäck et al., 1994). The higher binding cooperativity of the mutant was unexpected since the triple mutation (G458E, S459G, and V462A) is made in the recognition helix and distant from the dimerization surface which is formed by residues in the fragment A477-N491. Sequential and long-range NOE connectivities and measured 3JHNHalpha coupling constants indicate that the overall structures of the two proteins are very similar, possibly with a less well-defined structure of the fragment K486-N491 in GRDBDEGA. However, chemical shift changes, line broadening, and increased amide proton exchange rates are observed for several residues at, or close to, the dimerization surface of the mutant. These observations are interpreted as a lower stability and/or several slowly interconverting folded conformations of this region of GRDBDEGA. The effects are likely to be due to the loss of a hydrogen bond which links S459 to the dimerization region in GRDBD. Different mechanisms for the increased binding cooperativity of the mutant are discussed, and it is noted that the properties of the GRDBDEGA dimerization region are reminiscent of those reported for the estrogen receptor DBD, which also binds to an ERE site.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D011965 Receptors, Glucocorticoid Cytoplasmic proteins that specifically bind glucocorticoids and mediate their cellular effects. The glucocorticoid receptor-glucocorticoid complex acts in the nucleus to induce transcription of DNA. Glucocorticoids were named for their actions on blood glucose concentration, but they have equally important effects on protein and fat metabolism. Cortisol is the most important example. Corticoid Type II Receptor,Glucocorticoid Receptors,Glucocorticoids Receptor,Corticoid II Receptor,Corticoid Type II Receptors,Glucocorticoid Receptor,Receptors, Corticoid II,Receptors, Corticoid Type II,Receptors, Glucocorticoids,Corticoid II Receptors,Glucocorticoids Receptors,Receptor, Corticoid II,Receptor, Glucocorticoid,Receptor, Glucocorticoids
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D006860 Hydrogen Bonding A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. Hydrogen Bonds,Bond, Hydrogen,Hydrogen Bond
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D017433 Protein Structure, Secondary The level of protein structure in which regular hydrogen-bond interactions within contiguous stretches of polypeptide chain give rise to ALPHA-HELICES; BETA-STRANDS (which align to form BETA-SHEETS), or other types of coils. This is the first folding level of protein conformation. Secondary Protein Structure,Protein Structures, Secondary,Secondary Protein Structures,Structure, Secondary Protein,Structures, Secondary Protein

Related Publications

H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
DNA binding specificity of mutant glucocorticoid receptor DNA-binding domains.
February 1991, The Journal of biological chemistry,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
DNA-binding specificity of mutant glucocorticoid receptor DNA-binding domains.
June 1993, Annals of the New York Academy of Sciences,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
Backbone dynamics of the glucocorticoid receptor DNA-binding domain.
December 1992, Biochemistry,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
Solution structure of the glucocorticoid receptor DNA-binding domain.
July 1990, Science (New York, N.Y.),
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
Rational design of an estrogen receptor mutant with altered DNA-binding specificity.
January 2007, Nucleic acids research,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
Refined solution structure of the glucocorticoid receptor DNA-binding domain.
December 1993, Biochemistry,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
A comparison of 15N NMR relaxation measurements with a molecular dynamics simulation: backbone dynamics of the glucocorticoid receptor DNA-binding domain.
December 1993, Proteins,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
Cooperativity and specificity in the interactions between DNA and the glucocorticoid receptor DNA-binding domain.
June 1990, Biochemistry,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
A consensus motif in the RFX DNA binding domain and binding domain mutants with altered specificity.
August 1996, Molecular and cellular biology,
H Berglund, and M Wolf-Watz, and T Lundbäck, and S van den Berg, and T Härd
Conformational states of the glucocorticoid receptor DNA-binding domain from molecular dynamics simulations.
October 2002, Proteins,
Copied contents to your clipboard!