Crystal structures of highly specific phosphinic tripeptide enantiomers in complex with the angiotensin‐I converting enzyme

Abstract

Human somatic angiotensin‐I converting enzyme (ACE) is a zinc‐dependent dipeptidyl carboxypeptidase and a central component of the renin angiotensin aldosterone system (RAAS). Its involvement in the modulation of physiological actions of peptide hormones has positioned ACE as an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the crystal structures of the two catalytic domains of human ACE (N‐ and C‐) in complex with FI, the S enantiomer of the phosphinic ACE/ECE‐1 (endothelin converting enzyme) dual inhibitor FII, to a resolution of 1.91 and 1.85 Å, respectively. In addition, we have determined the structure of AnCE (an ACE homologue from Drosophila melanogaster) in complex with both isomers. The inhibitor FI (S configuration) can adapt to the active site of ACE catalytic domains and shows key differences in its binding mechanism mostly through the reorientation of the isoxazole phenyl side group at the P1′ position compared with FII (R configuration). Differences in binding are also observed between FI and FII in complex with AnCE. Thus, the new structures of the ACE–inhibitor complexes presented here provide useful information for further exploration of ACE inhibitor pharmacophores involving phosphinic peptides and illustrate the role of chirality in enhancing drug specificity.DatabaseStructural data are available in the Protein Data Bank databases under accession numbers 4ca5, 4ca6, 4ca7, 4ca8.

Human angiotensin I‐converting enzyme study by surface‐enhanced Raman spectroscopy

“…According to proposed ACE regions responsible for the binding to the silver surface, we assumed the preferential model of relative superposition of the two domains within somatic ACE molecule adsorbed on a silver substrate. This model was based on the crystal structures of individual domains (PDB 2C6F [ 48 ] and 4CA5 [ 89 ] ) (Figure 3). For the chosen orientation of the domains, sulfide bridges within both domains are located far from the surface of the substrate; thus, they do not give characteristic Raman bands for S‐S bonds (Figure 3a).…”

Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure

“…The crystal structures of both the ACE C domain and N domain in complex with these compounds unexpectedly reveal that the bulky P 1 ′ group is accommodated by the S 2 ′ pocket in all four structures, highlighting the fluidity between the S 1 ′ and S 2 ′ pockets and the S 2 ′ pocket’s ability to accommodate conformationally diverse, bulky hydrophobic groups (Fig. 6) (Akif et al, 2011; Masuyer et al, 2014). Another surprising finding was that an additional FII inhibitor molecule occupied the C-domain active site, binding on the nonprime side of the first molecule.…”

ACE2 and ACE: structure-based insights into mechanism, regulation and receptor recognition by SARS-CoV

“…Many ACE ligands have also been co-crystallised with the Drosophila melanogaster AnCE (Drosophila angiotensin converting enzyme) homologue, highlighting key differences in the active sites of ACE and AnCE [77][78][79][80][81][82]. Recently, the structure of A. gambiae AnoACE2 complexed to an ACE inhibitor was also solved, and active site comparisons revealed potential avenues for the development of AnoACE2-specific inhibitors for use as insecticides [83].…”