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The crystal structure of human procathepsin K
J M LaLonde1, B Zhao, C A Janson
1Department of Structural Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Biochemistry
|January 20, 1999
Summary
The structure of human procathepsin K reveals how its propeptide inhibits and stabilizes the enzyme. This finding aids understanding of cysteine protease activation in bone resorption.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Cathepsin K is a key cysteine protease in human osteoclasts, crucial for bone resorption.
- It is synthesized as an inactive proenzyme, activated by low pH via propeptide removal.
Purpose of the Study:
- To determine the high-resolution structure of human procathepsin K.
- To elucidate the molecular mechanisms underlying procathepsin K inhibition and activation.
Main Methods:
- X-ray crystallography was used to determine the structure of human procathepsin K at 2.8 Å resolution.
Main Results:
- The mature enzyme domain structure is nearly identical to mature cathepsin K.
- The propeptide occupies the active site cleft, stabilized by hydrophobic and electrostatic interactions.
- The propeptide fold shares similarities with other procathepsins, despite sequence variations.
Conclusions:
- The propeptide actively inhibits procathepsin K by occupying its active site.
- Structural insights explain the proenzyme's stability and provide a basis for understanding its activation.
- This research deepens the understanding of cysteine protease regulation and bone resorption mechanisms.