Cathepsin K expressed in osteoclasts possesses elastolytic and collagenolytic activities and plays a critical role in the bone remodeling process. It has been validated as a chemotherapeutic target for osteoporosis treatment. Cathepsin K is effectively inhibited by synthetic peptidomimetic compounds containing an azanitrile reactive warhead forming reversible interaction at subnanomolar concentrations. We prepared azanitrile inhibitor complexes with recombinant activated cathepsin K that were subjected to high-throughput crystallization screening. Here we present two crystal structures, determined at 1.9 Å resolution and describe for the first time the binding mode of the azanitrile scaffold to the active site of cysteine proteases.
Supported by project ChemBioDrug No. CZ.02.1.01/0.0/0.0/16_019/0000729 from European Regional Development Fund (OP RDE)