Desmoplakin is a protein in the desmosome that plays an integral role in connecting the intermediate filaments from one cardiomyocyte to another. Some desmoplakin mutations have been linked to arrhythmogenic cardiomyopathy and fragile skin disease. Specific mutations in DSP (R451G, S507F, S442F, and S299R) result in hypersensitive cleavage in the presence of the protease calpain. To block this cleavage event, we have screened drugs for their ability to specifically inhibit calpain-dependent DSP degradation. STD-NMR experiments further confirm that 12 of the drugs bind to DSP in the μM range. Here, we begin studies designed to interrogate where the most promising drugs bind to desmoplakin, using biomolecular crystallography and molecular dynamics simulation experiments.
McGinnis et al. (Sun,) studied this question.