Converting inactive peptides into potent transcriptional activators.
Significant efforts have been devoted to the development of artificial transcriptional activators for use as mechanistic tools, as therapeutic agents, and for biomanufacturing applications. One of the primary challenges has been the development of artificial activators that exhibit potency in cells comparable to that of endogenous activators; the vast majority function only moderately in the cellular context. Here we demonstrate that the superimposition of two distinct binding modes, a masking interaction and an interaction with the transcriptional machinery, has a profoundly positive effect on the cellular activity of artificial activators, with up to 600-fold enhancement observed. Incorporation of this feature into future generations of small molecule transcriptional activators should increase their nuclear uptake and facilitate their accessibility to their target proteins, thus significantly augmenting both their activity and utility.
Lum
Jenifer K
JK
Majmudar
Chinmay Y
CY
Ansari
Aseem Z
AZ
Mapp
Anna K
AK
D001671:Biochemistry / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004268:DNA-Binding Proteins / Q000737:chemistry; D005656:Fungal Proteins / Q000737:chemistry; D008024:Ligands; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D008024:Ligands; D010455:Peptides; D014157:Transcription Factors