title: Small-molecule switches for zinc finger transcription factors.
abstract: We have developed a general approach to generate selective small-molecule switches for zinc finger transcription factors based on the notion of structural complementation. A small molecule, 2-(4'-quinoline)benzimidazole (7), was identified by screening of a heterocycle library, which functionally rescues a structurally compromised transcription factor C7-F116A/H125G-VP16. Compound 7 induces the activity of the mutant zinc finger in a luciferase-based transactivation assay by about 18-fold at 100 muM concentration. Surface plasmon resonance measurements revealed that compound 7 enhances the affinity between the mutant C7 and its cognate DNA sequence by 16-fold while a structurally analogous compound, 2-(2'-naphthyl)benzimidazole (8), showed no affinity enhancement, indicating there is a specific interaction between compound 7 and the mutant zinc finger. Taken together, these results suggest that the partial affinity recovery of the mutant transcription factor may be the mechanism for the functional rescue of the zinc finger transcription factor by compound 7.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lin
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Barbas
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D000595:Amino Acid Sequence; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016335:Zinc Fingers / Q000187:drug effects / Q000235:genetics*
chemical_list: D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D014157:Transcription Factors