Volume 12, Issue 8, Pages (August 2005)

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Volume 12, Issue 8, Pages 883-893 (August 2005) A Functionally Orthogonal Estrogen Receptor-Based Transcription Switch Specifically Induced by a Nonsteroid Synthetic Ligand Paola Gallinari, Armin Lahm, Uwe Koch, Chantal Paolini, Maria Chiara Nardi, Giuseppe Roscilli, Olaf Kinzel, Daniela Fattori, Ester Muraglia, Carlo Toniatti, Riccardo Cortese, Raffaele De Francesco, Gennaro Ciliberto Chemistry & Biology Volume 12, Issue 8, Pages 883-893 (August 2005) DOI: 10.1016/j.chembiol.2005.05.018 Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 1 Design of a Compound-Specific ER-LBD Mutant Library (A) Structures of estradiol and representative active and inactive tetrahydrofluorenone analogs. Positions 4 and 9a, where substituents have been introduced, are indicated. (B) hERα-LBD mutant library. Molecular models of the three rotamers of CMP1 in the crystal structure of the hERα (PDB entry 1ERE) binding pocket. The five residues mutagenized in the library are shown together with G521. Left: solvent-accessible surface of CMP1. Right: space-filling representation highlighting the steric clashes between side chains and CMP1. Side chains of library residues are colored yellow. Chemistry & Biology 2005 12, 883-893DOI: (10.1016/j.chembiol.2005.05.018) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 2 Comparison of Chimeric Transcription Factors Containing wt hERα-LBD or hERα-L(384)M-LBD (A) Schematic representation of the GAL4DBD/hERα-LBD/VP16AD chimeric transcription factors. (B) Transcriptional activation in yeast transformants expressing chimeras based on wt hERα-LBD (squares) or hERα-L(384)M-LBD (circles) by E2 and the hERβ-specific compound CMP2. Dose-response curves of β-galactosidase activity in the presence of increasing concentrations of E2 or CMP2 were obtained. EC50 values were determined as described in Experimental Procedures. Chemistry & Biology 2005 12, 883-893DOI: (10.1016/j.chembiol.2005.05.018) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 3 Ligand-Dependent Transcriptional Activity of the M(421)G-Selected Mutant in the lacZ Reporter Yeast Strain Y187 Dose-response curves of β-galactosidase activity in the presence of increasing concentrations of E2 and the two tetrahydrofluorenone compounds CMP4 and CMP5 were determined for the L(384)M, M(421)G-selected mutant (squares) and for the L(384)M parental clone (circles). EC50 values were calculated as described in Experimental Procedures. Chemistry & Biology 2005 12, 883-893DOI: (10.1016/j.chembiol.2005.05.018) Copyright © 2005 Elsevier Ltd Terms and Conditions

Figure 4 Orthogonal Gene Switch in Mammalian Cells (A) Structures of representative “antagonistic chain”-substituted tetrahydrofluorenones. (B) Representative dose-response curves of chimeric transcription factor HEA-MGR to CMP8 (squares) and E2 (triangles). (C) HEA-MGR response to “antagonistic chain”-substituted tetrahydrofluorenones. Each data point represents the mean ± SD of three independent experiments. Chemistry & Biology 2005 12, 883-893DOI: (10.1016/j.chembiol.2005.05.018) Copyright © 2005 Elsevier Ltd Terms and Conditions