Crystal structure of human cathepsin S

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Human cathepsin S is a cysteine protease implicated in various biological processes.
• Understanding its structure is crucial for developing targeted inhibitors.
• Previous studies have characterized related cysteine proteases but lacked detailed structural information for cathepsin S-inhibitor complexes.

Purpose of the Study:

• To determine the high-resolution crystal structure of human cathepsin S in complex with a potent, irreversible inhibitor.
• To elucidate the binding interactions between the inhibitor and the enzyme's active site.
• To identify structural features that could be exploited for selective cathepsin S inhibition.

Main Methods:

• X-ray crystallography was used to determine the 2.5 Å structure of the cathepsin S-inhibitor complex.
• Data processing involved non-crystallographic symmetry averaging and density modification techniques.
• Refinement utilized methods to reduce parameter count for improved structural accuracy.

Main Results:

• The refined structure reveals human cathepsin S is similar to related cysteine proteases (e.g., papain, cathepsins K and L).
• The inhibitor is covalently attached to Cys 25, occupying subsites S3-S1'.
• A larger S2 pocket and the presence of Lys 61 in S3 and Arg 137 in S1' suggest opportunities for selective inhibition and provide insights into substrate specificity.

Conclusions:

• The determined structure provides a detailed atomic-level understanding of cathepsin S in complex with an irreversible inhibitor.
• Structural features like Lys 61 and Arg 137 are identified as potential targets for developing selective inhibitors.
• This structural information can guide the design of novel therapeutic agents targeting cathepsin S.