title: Distinct molecular conformations of the estrogen receptor alpha complex exploited by environmental estrogens.
abstract: We have advanced the view that estrogens activate the estrogen receptor (ER) alpha complex differently. A group of planar (estradiol, genistein, and coumestrol) and nonplanar (methoxychlor and its mono- and didemethylated phenolic metabolites) environmental estrogens, which are all full estrogens in MCF-7 breast cancer cell proliferation assays, was shown to segregate discretely into planar and nonplanar groups. These groups were delineated using a novel assay of mutant ER cDNAs stably transfected into MDA-MB-231 cells and the activation of the transforming growth factor alpha target gene in situ that putatively describes the external shape of the ER complex. Planar compounds activate estrogen action through the two traditional activation functions (AFs), AF1 and AF2, in the ER. In contrast, nonplanar compounds can activate estrogen action through AF1 and the amino acids Asp-351 and Asp-538, which are exposed when helix 12 silences AF2. The observation that class I (planar) and class II (nonplanar) compounds have different mechanisms of estrogen action may have important implications for tissue selective modulation of the ER.
authors: Robert H. Lurie Comprehensive Cancer Center, and Department of Surgery, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors: David
authors: D
authors: Bentrem
authors: Jennifer E
authors: JE
authors: Fox
authors: Sandra Timm
authors: ST
authors: Pearce
authors: Hong
authors: H
authors: Liu
authors: Sam
authors: S
authors: Pappas
authors: David
authors: D
authors: Kupfer
authors: James W
authors: JW
authors: Zapf
authors: V Craig
authors: VC
authors: Jordan
mesh_terms: D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha; D006801:Humans; D007529:Isoflavones / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D048789:Phytoestrogens; D028321:Plant Preparations / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D047628:Estrogen Receptor alpha; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen