%0 Journal Article
%T Structural definition and substrate specificity of the S28 protease family: the crystal structure of human prolylcarboxypeptidase
%A Stephen M Soisson
%A Sangita B Patel
%A Pravien D Abeywickrema
%A Noel J Byrne
%A Ronald E Diehl
%A Dawn L Hall
%A Rachael E Ford
%A John C Reid
%A Keith W Rickert
%A Jennifer M Shipman
%A Sujata Sharma
%A Kevin J Lumb
%J BMC Structural Biology
%D 2010
%I BioMed Central
%R 10.1186/1472-6807-10-16
%X The experimentally phased 2.8 £¿ crystal structure is presented for human PRCP. PRCP contains an ¦Á/¦Â 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.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.Proteases are an important class of enzymes involved in a diverse range of physiological processes. The modulation of proteolytic activity is an established means of therapeutic intervention with currently marketed products for afflictions as diverse as type 2 diabetes, hypertension and viral infections. The human protease tree is comprised of at least 676 diverse proteins that have been systematically organized into clans and families based on similarity in sequence, structure, and function [1]. Although the structural basis of catalytic mechanism, substrate specificity and rational drug design has been identified for numerous protease families, there has been no structural description of the S28 family of proteases that form a distinct branch of the serine carboxypeptidase clan.The S28 family of peptidases consists of two enzymes, PRCP and DPP7. DPP7 is also called dipeptidyl peptidase 2 and quiescent cell proline dipeptidase [2-4]. PRCP is a lysosomal, serine carboxypeptidase that c
%U http://www.biomedcentral.com/1472-6807/10/16