3d models of mbp, a biologically active metabolite of bisphenol a, in human estrogen receptor α and estrogen receptor βmbp的3 d模型,双酚a的生物活性代谢物,在人类雌激素受体α和雌激素受体β.pdfVIP

3D Models of MBP, a Biologically Active Metabolite of Bisphenol A, in Human Estrogen Receptor a and Estrogen Receptor b 1 2 Michael E. Baker *, Charlie Chandsawangbhuwana 1 Department of Medicine, University of California San Diego, La Jolla, California, United States of America, 2 Department of Bioengineering, University of California San Diego, La Jolla, California, United States of America Abstract Bisphenol A [BPA] is a widely dispersed environmental chemical that is of much concern because the BPA monomer is a weak transcriptional activator of human estrogen receptor a [ERa] and ER b in cell culture. A BPA metabolite, 4-methyl-2,4- bis(4-hydroxyphenyl)pent-1-ene [MBP], has transcriptional activity at nM concentrations, which is 1000-fold lower than the concentration for estrogenic activity of BPA, suggesting that MBP may be an environmental estrogen. To investigate the structural basis for the activity of MBP at nM concentrations and the lower activity of BPA for human ERa and ERb, we constructed 3D models of human ERa and ERb with MBP and BPA for comparison with estradiol in these ERs. These 3D models suggest that MBP, but not BPA, has key contacts with amino acids in human ERa and ERb that are important in binding of estradiol by these receptors. Metabolism of BPA to MBP increases the spacing between two phenolic rings, resulting in contacts between MBP and ERa and ERb that mimic those of estradiol with these ERs. Mutagenesis of residues on these ERs that contact the phenolic hydroxyls will provide a test for our 3D models. Other environmental chemicals containing two appropriately spaced phenolic rings and an aliphatic spacer instead of an estrogenic B and C rin