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The X-prolyl dipeptidyl aminopeptidase (X-PDAP) from Lactococcus lactis is a dimeric enzyme catalyzing the removal of Xaa-Pro dipeptides from the N terminus of peptides. The structure of the enzyme was solved at 2.2 A resolution and provides a model for the peptidase family S15. Each monomer is composed of four domains. The larger one presents an alpha/beta hydrolase fold and comprises the active site serine. The specificity pocket is mainly built by residues from a small helical domain which is, together with the N-terminal domain, essential for dimerization. A C-terminal moiety probably plays a role in the tropism of X-PDAP toward the cellular membrane. These results give new insights for further exploration of the role of the enzymes of the SC clan.

Disufide-bond isomerase (DsbC) plays a crucial role in folding periplasmically excreted bacterial proteins. The crystal structure of the reduced form of DsbC is presented. The pair of thiol groups from Cys98 and Cys101 that form the reversible disulfide bond in the enzymatic active site are 3.1 A apart and the electron density clearly shows that the S atoms do not form a covalent bond. The other pair of Cys residues (141 and 163) in DsbC form a disulfide bond. This is different from the previously reported crystal form of DsbC (McCarthy et al., 2000), in which both Cys pairs are oxidized. Specific hydrogen-bond interactions are identified that stabilize the active site in the reactive reduced state with the special participation of hydrogen bonds between the active-site cysteine residues (98 and 101) and threonine residues 94 and 182. The present structure also differs in the orientation of the catalytic domains within the protein dimer. This is evidence of flexibility within the protein that probably plays a role in accommodating the substrates in the cleft between the catalytic domains.

Background:Little is known about the cancer dependence and druggability of PRP4. Results: Significance of PRP4 catalytic activity is demonstrated, novel substrates are identified, and features of kinase domain structure are revealed. Conclusion: PRP4 is required for cancer cell survival, displays substrate specificity, and is amenable to pharmacological inhibition. Significance: Our results indicate that PRP4 is a potential drug target to pursue in cancer.