title: Synthetic 19-nortestosterone derivatives as estrogen receptor alpha subtype-selective ligands induce similar receptor conformational changes and steroid receptor coactivator recruitment than natural estrogens.
abstract: The binding of estradiol (E(2)) to estrogen receptors (ER) is followed by conformational changes resulting in coactivator or corepressor recruitment that influences gene transcription. A series of synthetic A-ring reduced 19-nortestosterone-derived progestins has the capacity to selectively bind and activate transcription through the ERalpha. Herein, the molecular mechanisms involved in ER subtype-selective interactions of these compounds as assessed by their effects upon both ERalpha and ERbeta structural conformation and their ability to induce recruitment of steroid receptor coactivator-1 (SRC-1) to ERalpha were investigated. The results demonstrated that all synthetic A-ring 3beta,5alpha-tetrahydro-reduced derivatives of 19-nortestosterone induced an ERalpha trypsin digestion pattern similar to that seen with E(2), without effects upon ERbeta. In addition, these compounds had the ability to recruit SRC-1 to the ligand-binding domain of ERalpha similar to E(2). Our data indicate that A-ring 3beta,5alpha-tetrahydro-reduced 19-nortestosterone-derived progestins behave as selective ERalpha agonists with ligand-receptor structural and functional responses similar to those induced with natural E(2).
authors.affiliation: Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No. 15, Mexico City 14000, Mexico.
authors.forename: Rocio
authors.initials: R
authors.lastname: García-Becerra
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Borja-Cacho
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Cooney
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Smith
authors.forename: Ana E
authors.initials: AE
authors.lastname: Lemus
authors.forename: Gregorio
authors.initials: G
authors.lastname: Pérez-Palacios
authors.forename: Fernando
authors.initials: F
authors.lastname: Larrea
mesh_terms: D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D000077267:Fulvestrant; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D056920:Nuclear Receptor Coactivator 1; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D011487:Protein Conformation; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011987:Receptors, Steroid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014357:Trypsin / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011372:Progestins; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D014157:Transcription Factors; D000077267:Fulvestrant; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; D009277:Nandrolone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D014357:Trypsin