Title : Structural definition and substrate specificity of the
S28 protease family: the crystal structure of human
prolylcarboxypeptidase
Abstract :
- BACKGROUND: The unique S28 family of proteases is comprised of the carboxypeptidase PRCP and the aminopeptidase DPP7
- The structural basis of the different substrate specificities of the two enzymes is not understood nor has the structure of the S28 fold been described
- RESULTS: The experimentally phased 2.8 A crystal structure is presented for human PRCP
- PRCP contains an alpha/beta hydrolase domain harboring the catalytic Asp-His-Ser triad and a novel helical structural domain that caps the active site
- Structural comparisons with prolylendopeptidase and DPP4 identify the S1 proline binding site of PRCP
- A structure-based alignment with the previously undescribed structure of DPP7 illuminates the mechanism of orthogonal substrate specificity of PRCP and DPP7
- PRCP has an extended active-site cleft that can accommodate proline substrates with multiple N-terminal residues
- In contrast, the substrate binding groove of DPP7 is occluded by a short amino-acid insertion unique to DPP7 that creates a truncated active site selective for dipeptidyl proteolysis of N-terminal substrates
- CONCLUSION: The results define the structure of the S28 family of proteases, provide the structural basis of PRCP and DPP7 substrate specificity and enable the rational design of selective PRCP modulators