Glutaminyl Cyclases have been identified as catalysts of pyroglutamyl formation at the N-terminus of A�-peptides deposited in Alzheimers Disease. The modification enforces amyloidogenicity, likely contributing to progression of the disorder. Inhibitors of QC attenuated AD-like pathology in animal models of AD. We characterized the binding mode of the inhibitor PBD150 applying a combined approach of in-silico analysis and site directed mutagenesis. PBD150 co-crystallized with QCs reveals different poses of a derivatized phenyl ring. These poses were characterized via a semi-empirical approach based on the linear-scaling divide-and-conquer methodology, and further analyzed using the SE-COMBINE approach. Following this approach, site directed mutagenesis was performed to replace key amino acids of the active site. In contrast to metal binding groups, the Ki-values of PDB150 are affected drastically for some variants, suggesting a specific probing of secondary interactions between PBD150 and QC.

Probing secondary Glutaminyl-Cyclase (QC)-inhibitor interactions applying an in silico-analysis/site-directed mutagenesis approach

243rd National Meeting (2012)

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