Structural Analysis of the Putative Succinyl-Diaminopimelic Acid Desuccinylase DapE from Campylobacter jejuni: Captopril-Mediated Structural Stabilization

DapE is a highly conserved bacterial enzyme that produces L,L-diaminopimelic acid in the <i>meso</i>-diaminopimelic acid and lysine synthesis pathway, which is essential for peptidoglycan formation in the cell wall. DapE has been recognized as a promising antibacterial drug target and can be inhibited by captopril. The pathogenic bacterium <i>Campylobacter jejuni</i> expresses a DapE ortholog, cjDapE. However, the structural basis underlying the enzymatic activity of cjDapE and its inhibition by captopril is unknown. Here, we report the crystal structures of cjDapE in complexes with Zn²⁺ and with both Zn²⁺ and captopril. cjDapE consists of a catalytic domain (CD) and a dimerization domain (DD). The CD harbors a pocket, which accommodates two Zn²⁺ ions in close proximity as the catalytic active site. cjDapE assembles into a dimer primarily using DD residues, with two DD loops largely disordered in the absence of captopril. Upon captopril binding, these loops become ordered and contribute to dimer stabilization by involving both DD and CD residues. Notably, captopril binding maintains cjDapE in an open conformation that is incompatible with catalytic activity. Our comparative structural analysis suggests that captopril inhibits cjDapE primarily via substrate competition.