[2P-64*] 転写コアクチベーターCBPのKIXドメインと転写アクチベーターの相互作用を標的とした合理的な阻害剤設計
Protein-protein interactions (PPIs) are involved in various diseases. Therefore, designing inhibitors of PPIs is a promising way for drug discovery. The PPIs of the KIX domain of the transcriptional coactivator CREB-binding protein (CBP) with transcriptional activators may cause leukemia and various viral diseases. To develop the inhibitor of the PPIs, we used the transactivation domain (TAD) of the transcriptional activator mixed lineage leukemia protein (MLL) as a template. Using the protein design software Rosetta, we theoretically designed the mutants of the MLL TAD fragment that may bind KIX more tightly than the wild type. Among the mutants, we selected 11 mutants that have higher helicity than the wild type using the helicity prediction algorithm AGADIR. The mutants of the MLL TAD fragment were expressed in E. coli, and their binding affinities to KIX were measured by isothermal titration calorimetry. We found that the designed mutants bind KIX more tightly than the wild-type. In particular, the mutant with the highest binding affinity can bind KIX two-fold more tightly than the wild-type. Thus, this strategy may be useful for designing PPI inhibitors.