Drug-controlled systems and uses thereof
The technology described herein is directed to polypeptide systems using drug-controlled peptide docking domains and cognate docking domain-binding peptides and their use to control cellular signaling, activity, and/or gene expression.
1 . A system comprising:
a) a first polypeptide which is a transmembrane polypeptide, the first polypeptide comprising:
i) an extracellular receptor, wherein the extracellular receptor is LaG17;
ii) an extracellular localization domain, wherein the extracellular localization domain is CD8a;
iii) a Notch receptor regulatory domain (NRR), wherein the NRR has a sequence that is at least 95% identical to SEQ ID NO: 190 or 191;
iv) a Notch transmembrane domain;
v) a cognate docking domain-binding peptide, wherein the cognate docking domain-binding peptide is CP5-46-4D5E; and
vi) a first member of a pair of activity-complementing domains; and
b) a second polypeptide comprising:
i) a drug-controlled peptide docking domain, wherein the drug-controlled peptide docking domain is hepatitis C virus (HCV) nonstructural protein 3 (NS3); and
ii) a second member of the pair of activity-complementing domains,
wherein the first and second member of the pair of activity-complementing domains comprises a Gal4 DNA-binding domain and a transcriptional effector domain, respectively.
2 . The system of claim 1 , wherein the
transcriptional effector domain is a VPR transcriptional effector domain or KRAB transcriptional repressor domain.
3 . The system of claim 1 , further comprising a cell expressing the first and second polypeptides.
4 . The system of claim 1 , further comprising a drug that controls the drug-controlled peptide docking domain.
5 . The system of claim 4 , wherein
the drug is selected from the group consisting of: grazoprevir, glecaprevir, danoprevir, asunaprevir, telaprevir, boceprevir, simeprevir, paritaprevir, voxilaprevir, narlaprevir, and ciluprevir.