The lysosomal cysteine proteases

A significant number of exciting papain-like cysteine protease structures h ave been determined by crystallographic methods over the last several years . This trove of data allows for an analysis of the structural features that empower these molecules as they efficiently carry out their specialized ta sks. Although the structure of the paradigm for the family, papain, has bee n known for twenty years, recent efforts have reaped several structures of specialized mammalian enzymes. This review first covers the commonalities o f architecture and purpose of the papain-like cysteine proteases. From that broad platform, each of the lysosomal enzymes for which there is an X-ray structure (or structures) is then examined to gain an understanding of what structural features are used to customize specificity and activity. Struct ure-based design of inhibitors to control pathological cysteine protease ac tivity will also be addressed.