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Open Access Highly Accessed Research article

Structural definition and substrate specificity of the S28 protease family: the crystal structure of human prolylcarboxypeptidase

Stephen M Soisson*, Sangita B Patel, Pravien D Abeywickrema, Noel J Byrne, Ronald E Diehl, Dawn L Hall, Rachael E Ford, John C Reid, Keith W Rickert, Jennifer M Shipman, Sujata Sharma and Kevin J Lumb*

Author Affiliations

Global Structural Biology, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA

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BMC Structural Biology 2010, 10:16  doi:10.1186/1472-6807-10-16

Published: 11 June 2010

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 Å crystal structure is presented for human PRCP. PRCP contains an α/β 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.