The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: How receptors discriminate between their response elements

Schwabe, John W. R.; Chapman, Lynda; Finch, J.T.; Rhodes, Daniela

doi:10.1016/0092-8674(93)90390-c

Cited by 687 publications

(549 citation statements)

References 45 publications

Supporting

Mentioning

511

Contrasting

Unclassified

Order By: Relevance

“…We used the structure of the ER-β bound to a DNA response element (pdb code 1HCQ) as a template. 18 We built models for dimers of the wild-type DBD with and without DNA. A model for the p.(Asn181del) (N181del) mutation (found in case 1) was built in YASARA Structure based on the wild-type model, by deleting residue N181 and introducing a new peptide bond between residues 180 and 182, followed by energy minimization (the em_runclean protocol in YASARA Structure).…”

Section: Structural Analysis Of the Estrogen Receptor-β (Er-β) Variantsmentioning

confidence: 99%

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Baetens

Güran

Mendonça

et al. 2018

Genetics in Medicine

View full text Add to dashboard Cite

Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.

show abstract

Section: Structural Analysis Of the Estrogen Receptor-β (Er-β) Variantsmentioning

confidence: 99%

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Baetens

Güran

Mendonça

et al. 2018

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…The DNAbinding domain binds specifically to hormone-responsive elements in DNA. The structural basis of DNA recognition is well established from nuclear magnetic resonance and X-ray crystallography analyses [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Large-scale expression and purification of the human vitamin D receptor and its ligand-binding domain for structural studies

Juntunen

Rochel

Moras

et al. 1999

Biochemical Journal

View full text Add to dashboard Cite

We have expressed recombinant human vitamin D receptor and its ligand-binding domain in Spodoptera frugiperda (Sf9) insect cells with a 30-litre bioreactor. Both proteins were purified to apparent homogeneity with yields of 0.5-3.5 mg\l. Gel-filtration analyses indicated that the purified human vitamin D receptor and its ligand-binding domain were present as monomers in solution. The purified vitamin D receptor and its ligand-binding domain were demonstrated to bind 1α,25-dihydroxyvitamin D $ with high affinity, the K d values ranging from 0.9 to 1.2 nM. Neutron scattering studies of the ligand-binding domain demonstrated that the samples are homogeneous and contain monomeric species of polypeptides. The purified vitamin D receptor

show abstract

“…Sequence-Structural modeling indicates that the base pairs in the DNA half-site are contacted through a web of multiple interactions with amino acids in both the P-and A-box of the receptor (12)(13)(14). These multiple protein-base-specific DNA contacts, both direct and through immobilized water molecules, might be expected to impose a strict DNA sequence specificity on these receptors.…”

Section: The C-erba Protein Exhibits a Broad Ability To Accommodate Hmentioning

confidence: 99%

“…Recognition of the sequence of each half-site has generally been believed to be mediated exclusively by a zinc-finger motif within the center of each receptor ( Fig. 1) (12)(13)(14). Amino acids in the P-box helix within this zinc-finger motif make direct contact with bases in the major grove of the DNA half-site, and altering amino acids in the P-box can alter the half-site specificity of the receptor (14 -22).…”

mentioning

confidence: 99%

DNA Recognition by Normal and Oncogenic Thyroid Hormone Receptors

Judelson

Privalsky

1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

The nuclear hormone receptors regulate target gene expression in response to hormones of extracellular origin. The DNA binding specificity of these receptors therefore plays the critical role of defining the precise repertoire of target genes that respond to a given hormone. We report here an analysis of the DNA binding specificity of the thyroid hormone receptor (c-ErbA protein) and that of an oncogenic derivative, the v-ErbA protein. These otherwise closely similar proteins exhibit quite divergent DNA sequence specificities at multiple positions within the DNA binding site. The thyroid hormone receptor (c-ErbA protein) exhibits a particularly broad DNA specificity, whereas the v-ErbA protein is comparatively quite specific. Intriguingly, these differences in DNA recognition largely map to an N-terminal receptor domain not traditionally implicated in DNA binding, and are further influenced by heterodimer formation with retinoid X receptors. We propose that the N terminus of nuclear hormone receptors plays an critical role in DNA recognition by altering the conformation of the receptor domains that make the actual base-specific contacts.The nuclear hormone receptors are a family of ligand-regulated transcription factors that mediate cellular responses to a broad range of small hydrophobic hormones (1-5). Members of the family include the steroid receptors, the retinoid acid receptors (RARs), 1 retinoid X receptors (RXRs), and the thyroid hormone receptors (T 3 Rs). Additional diversity is generated within individual receptor classes by the expression of multiple receptor isoforms; for example, T 3 Rs are encoded by two separate loci, ␣ and ␤ (3, 4). Despite this diversity, the different nuclear hormone receptors share a common mode of action, functioning by binding to specific DNA sequences and regulating expression of nearby target genes (1-4, 6, 7).The DNA recognition properties of each receptor play the critical role of defining the specific repertoire of target genes that respond to a given hormone. Most receptors bind to DNA as protein dimers, with each receptor molecule binding to a "half-site," a conserved 6 -8-nucleotide DNA sequence (7-11). Recognition of the sequence of each half-site has generally been believed to be mediated exclusively by a zinc-finger motif within the center of each receptor (Fig. 1) (12-14). Amino acids in the P-box helix within this zinc-finger motif make direct contact with bases in the major grove of the DNA half-site, and altering amino acids in the P-box can alter the half-site specificity of the receptor (14 -22). An additional ␣-helix, the A-box located at the C-terminal extreme of the zinc-finger motif, makes minor groove contacts with bases at the 5Ј end of the half-site (14, 23).Aberrant forms of nuclear hormone receptors are involved in several forms of cancer. The v-erbA oncogene, for example, is a mutated copy of the host cell gene (c-erbA) for T 3 R␣-1 (24, 25). V-ErbA has sustained a number of mutations relative to its T 3 R␣ progenitor (Fig. 1); as a result, v-ErbA...

show abstract

The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: How receptors discriminate between their response elements

Cited by 687 publications

References 45 publications

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Large-scale expression and purification of the human vitamin D receptor and its ligand-binding domain for structural studies

DNA Recognition by Normal and Oncogenic Thyroid Hormone Receptors

Contact Info

Product

Resources

About