title: Peptide binding identifies an ERalpha conformation that generates selective activity in multiple in vitro assays.
abstract: Drugs such as tamoxifen, which act at the estrogen receptor (ER), have very different in vitro and in vivo effects from those of the native hormone. Previous research has established that different ligands induce distinct conformational changes in the ER, thus affecting the interactions of the receptor with cell-specific co-activating or co-repressing proteins (cofactors) and estrogen response elements (EREs), thus potentially driving differing biological effects. Affinity-selected peptides have been used to probe the conformational changes that occur within the ER upon binding various ligands. In this study, the authors characterize the ability of several peptides to be recruited to liganded ER under cellular conditions. Approximating ER conformation via recruitment of this peptide to the ER is concluded to be a better predictor of the agonist nature of an ER ligand under these different cellular contexts than is a canonical cotransfection transactivation assay.
authors.affiliation: Department of Molecular & Cell Biology and New Leads Discovery Ligand Pharmaceuticals, San Diego, CA 92121, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Larson
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Osburn
authors.forename: Katherine
authors.initials: K
authors.lastname: Schmitz
authors.forename: Leslie
authors.initials: L
authors.lastname: Giampa
authors.forename: Shau-Ming
authors.initials: SM
authors.lastname: Mong
authors.forename: Keith
authors.initials: K
authors.lastname: Marschke
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosen
authors.forename: Andrés
authors.initials: A
authors.lastname: Negro-Vilar
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002522:Chlorocebus aethiops; D004353:Drug Evaluation, Preclinical; D004345:Drug Industry / Q000379:methods*; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D046911:Macromolecular Substances; D008954:Models, Biological; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D046911:Macromolecular Substances; D010455:Peptides; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000469:Alkaline Phosphatase