Development and validation of a homology model of human cathepsin H including the mini-chain

Cathepsin H is involved in intracellular protein degradation and is implica ted in a variety of physiological processes such as proenzyme activation, e nzyme inactivation, hormone maturation, tissue remodeling, and bone matrix resorption. A model of the tertiary structure of the human lysosomal cystei ne protease cathepsin H was constructed. The protein structure was built fr om its amino acid sequence and its homology to papain, actinidin, and cathe psin L for which crystallographic co-ordinates are available. The model was generated using the COMPOSER module of SYBYL. The position and interaction behavior of the so called mini-chain, the octa peptide EPQNCSAT, to the active-site cleft of cathepsin H could be determin ed by docking studies. Refinement was achieved through interactive visual a nd algorithmic analysis and minimization with the TRIPOS force field. The m odel was found to correlate with observed empirical data regarding ligand s pecificity. The model defines possible steric, hydrophobic, and electrostat ic interactions. We anticipate that the model will serve as a tool to under stand substrate specificity and may be used for the development of new spec ific ligands.