Three-dimensional structures of the cysteine proteases cathepsins K and S deduced by knowledge-based modelling and active site characteristics

Human cathepsins K and S are recently identified proteins with high primary sequence homology to members of papain superfamily, including cathepsins B , L, H and papain. Models of the tertiary structures of cathepsins K and S and their complexes with a specific substrate and inhibitor were constructe d and compared with the recently determined X-ray structure of cathepsin K. A major problem in the determination of the three-dimensional structure of proteins concerns the quality of the structural models obtained from the i nterpretation of experimental data. The framework of the tertiary structure s of cathepsins K and S consisted of structurally conserved regions from th e tertiary structure of the papain superfamily and the variable regions wer e constructed with fragments of other proteins from the protein data base. Based on docking studies the non-bonded interaction energies of ligands wit h the cathepsins were estimated. These energies correlate with experimental ly determined substrate and inhibitory potency.