Crystal structure of Drosophila angiotensin I‐converting enzyme bound to captopril and lisinopril1

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Abstract
Angiotensin I‐converting enzymes (ACEs) are zinc metallopeptidases that cleave carboxy‐terminal dipeptides from short peptide hormones. We have determined the crystal structures of AnCE, a Drosophila homolog of ACE, with and without bound inhibitors to 2.4 Å resolution. AnCE contains a large internal channel encompassing the entire protein molecule. This substrate‐binding channel is composed of two chambers, reminiscent of a peanut shell. The inhibitor and zinc‐binding sites are located in the narrow bottleneck connecting the two chambers. The substrate and inhibitor specificity of AnCE appears to be determined by extensive hydrogen‐bonding networks and ionic interactions in the active site channel. The catalytically important zinc ion is coordinated by the conserved Glu395 and histidine residues from a HExxH motif.