Ligand activated transcriptional regulator proteins
AssigneesThe Scripps Research Institute, Novartis AG
InventorsCarlos F. Barbas, III, Michael Joseph Kadan, Roger Beerli
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Abstract
Fusion proteins for use as ligand-dependent transcriptional regulators are provided. The fusion proteins include a nucleotide binding domain operatively linked to a ligand-binding domain. They also can include a transcription regulating domain. The nucleotide binding domain is a zinc-finger peptide that binds to a targeted contiguous nucleotide sequence of from 3 to about 18 nucleotides are provided. The fusion proteins are used for gene therapy. Also provided are polynucleotides encoding the fusion proteins, expression vectors, and transfected cells.
Claims34
A nucleic acid molecule, comprising a sequence of nucleotides encoding the fusion protein, wherein:
- the fusion protein comprises a nucleotide binding domain (DBD) operatively linked to a modified ligand binding domain (LBD) from an intracellular receptor:
- the fusion protein is a ligand activated transcriptional regulator;
- the nucleotide binding domain is a polydactyl zinc-finger domain that contains at least three modular portions thereof;
- each modular portion of the nucleotide binding domain interacts with a contiguous sequence of nucleotides of at least 3 nucleotides;
- and
- the ligand specificity of the LBD for endogenous and exogenous ligands is modified to change its ligand specificity compared to the ligand specificity of the ligand binding domain of the native intracellular receptor, whereby ligands that activate the fusion protein are not the ligands that activate the receptor from which the LBD was derived.
Dependencies are inferred from the claim text.