Description:
Altered levels of gene expression during cell development are associated with numerous debilitating human diseases, such as blood disorders. As a result, there is considerable interest in developing artificial transcription activators (ATA) that can efficiently and accurately reactivate gene expression in vivo. Such agents could be used both as therapeutic agents for treating diseases and as probes for understanding cell development. An ATA must minimally contain a DNA-binding domain (DBD) that binds a target site and an activation domain (TAD) that participates in interactions with the transcriptional machinery. Designing artificial TADs is extremely challenging due to the fact that TADs are intrinsically disordered domains. This intrinsic flexibility makes TADs very difficult to crystallize, and as a result there are a limited number of structures of TADs from which to base designs. Recently, the structures of the p53 and VP16 TADs in complex with a common target (TFIIH) by NMR spectroscopy have been determined. Starting from these information the research activity at IBB (in collaboration with Prof. J. Omichinski, Canada) consists of structure-based design of short, but highly active TAD motifs for the ultimate goal of developing a highly effective and accurate in vivo transactivation tool for incorporation into the ATAs