41 research outputs found
Bisphenol AF Is a Full Agonist for the Estrogen Receptor ERĪ± but a Highly Specific Antagonist for ERĪ²
Direct Evidence Revealing Structural Elements Essential for the High Binding Ability of Bisphenol A to Human Estrogen-Related Receptor-Ī³
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Effect of phosphorylation on the structure and fold of transactivation domain of p53
Several phosphorylations are known to occur in the N-terminal transactivation domain of human p53. To explore the structural effects of these phosphorylations, we have chemically synthesized the unphosphorylated p53-(1-39) and its three phosphorylated analogs, phosphorylated at Ser-15, Thr-18, and Ser-20. p53-(1-39) and its Ser-15 and Thr-18 phosphorylated analogs were tested for interaction with p300. The order of binding affinities was similar to that derived from biochemical experiments with the whole protein, indicating functional integrity of the domain. Differences in chemical shifts and coupling constants indicate significant structural changes upon phosphorylations. The single tryptophan in the unphosphorylated domain has an emission maximum and a Stern-Volmer constant that are characteristics of tryptophans situated in protein interiors. The diffusion constant is monomer-like, with an axial ratio of 1:7.5, indicating a significant degree of compaction. Upon phosphorylations, the emission maximum and diffusion constant change significantly toward values that indicate more open conformations. Binding of the hydrophobic probe bis-1-anilino-8-naphthalenesulfonate to the unphosphorylated and one of the phosphorylated domains is also significantly different, suggesting different conformations. We propose that phosphorylations switch the largely folded transactivation domain to more open conformations that interact with transcription factors such as p300/cAMP- responsive element-binding protein-binding protein, leading to enhancement of gene expression
Shimohigashi Y. Distinction of the binding modes for human nuclear receptor ERRgamma between bisphenol A and 4-hydroxytamoxifen
An in vivo Multi-Generation Propagation Assay for Endocrine Disrupting Chemicals in the Fruit Fly Drosophila melanogaster : Reproductive Functions Disrupted by 4-Nonylphenol
Bisphenol-C is the strongest bifunctional ERĪ±-agonist and ERĪ²-antagonist due to magnified halogen bonding.
We reported that bisphenol AF (BPAF) works as an agonist for estrogen receptor (ER) ERĪ± but as an antagonist for ERĪ². Similar results were observed for bisphenol E analogs (BPE-X) such as BPE-F, BPE-Cl, and BPE-Br, each consisting of a series of a tri-halogenated methyl group CX3 in the central alkyl moiety. It was demonstrated that the electrostatic halogen bond based on the dispersion force of halogen atoms is a major driving force in the activities of bifunctional ERĪ±-agonist and ERĪ²-antagonist. Since the chlorine atoms present in bisphenol C (BPC) exist in a Ļ-Ļ conjugated system due to the presence of an adjacent C = C double bond, we intended to prove that BPC is also a bifunctional ERĪ±-agonist and ERĪ²-antagonist exhibiting greatly enhanced agonist/antagonist activities. BPC was evaluated for its ability to activate ERĪ± and ERĪ² in the luciferase reporter gene assay using HeLa cells. With high receptor-binding ability to both ERs, BPC was found to be fully active for ERĪ± but inactive for ERĪ². BPC's definite antagonist activity in ERĪ² was revealed by its inhibitory activity against 17Ī²-estradiol. Thus, BPC is a bifunctional ERĪ±-agonist and ERĪ²-antagonist. These agonist/antagonist activities were discovered to be extremely high among series of halogen-containing bisphenol compounds. This comparative structure-activity study revealed that the ascending order of ERĪ±-agonist and ERĪ²-antagonist activities was BPE-F āŖ BPE-Cl ā² BPAF C = CCl2 double bond
An in vivo Multi-Generation Propagation Assay for Endocrine Disrupting Chemicals in the Fruit Fly Drosophila melanogaster : Reproductive Functions Disrupted by 4-Nonylphenol
A Characteristic Back Support Structure in the Bisphenol A-Binding Pocket in the Human Nuclear Receptor ERRĪ³
<div><p>The endocrine disruptor bisphenol A (BPA) affects various genes and hormones even at merely physiological levels. We recently demonstrated that BPA binds strongly to human nuclear receptor estrogen-related receptor (ERR) Ī³ and that the phenol-A group of BPA is in a receptacle pocket with essential amino acid residues to provide structural support at the backside. This led BPA to bind to ERRĪ³ in an induced-fit-type binding mode, for example, with a rotated motion of Val313 to support the Tyr326-binding site. A similar binding mechanism appears to occur at the binding site of the BPA phenol-B ring. X-ray crystal analysis of the ERRĪ³-ligand-binding domain/BPA complex suggested that the ERRĪ³ receptor residues Leu342, Leu345, Asn346, and Ile349 function as intrinsic binding sites of the BPA phenol-B, whereas Leu265, Leu268, Ile310, Val313, Leu324, Tyr330, Lys430, Ala431, and His434 work as structural elements to assist these binding sites. In the present study, by evaluating the mutant receptors replaced by a series of amino acids, we demonstrated that a finely assembled structural network indeed exists around the two adjacent Leu<sup>342</sup>-Asn<sup>346</sup> and Leu<sup>345</sup>-Ile<sup>349</sup> ridges on the same Ī±-helix 7 (H7), constructing a part of the binding pocket structure with back support residues for the BPA phenol-B ring. The results reveal that the double-layer binding sites, namely, the ordinary ligand binding sites and their back support residues, substantiate the strong binding of BPA to ERRĪ³. When ERRĪ³-Asn346 was replaced by the corresponding Gly and Tyr in ERRĪ± and ERRĪ², respectively, the binding affinity of BPA and even 4-hydroxytamxifen (4-OHT) is much reduced. Asn346 was found to be one of the residues that make ERRĪ³ to be exclusive to BPA.</p></div
The homologous competitive binding assays between [<sup>3</sup>H]bisphenol A and non-labeled bisphenol A for the wild-type ERRĪ³-LBD and its mutants.
<p>The receptors used were the wild-type ERRĪ³ and its mutant receptors. (<b>A</b>) Leu342-substituted ERRĪ³ mutant receptors, (<b>B</b>) Leu345-substituted ERRĪ³ mutant receptors, (<b>C</b>) Asn346-substituted ERRĪ³ mutant receptors, and (<b>D</b>) Ile349-substituted ERRĪ³ mutant receptors. The graphs show representative dose-dependent binding curves, which give the IC<sub>50</sub> value closest to the mean IC<sub>50</sub> from at least three independent experiments.</p
Receptor binding potency of BPA, 4-Ī±-cumylphenol, and 4-OHT in the competitive binding assay using [<sup>3</sup>H]BPA for human nuclear receptor ERRĪ³ and its mutants with site-directed mutagenesis in the BPA binding site amino acid residues.
1)<p>Specifically mutated residues are designated in italics.</p>2)<p>Because there was "no specific binding" in the saturation binding assay, the competitive binding assay could not be carried out.</p