Crystal structures of sampatrilat and sampatrilat‐Asp in complex with human ACE – a molecular basis for domain selectivity

• DOI: 10.1111/febs.14421
• Publication Date: 2018-02-24T13:22:35Z
• Authors: Gyles E. Cozier; Sylva L. Schwager; Rajni K. Sharma; Kelly Chibale; Edward D. Sturrock; K. Ravi Acharya
• Keywords: Affinities; Binding affinities

Angiotensin-1-converting enzyme (ACE) is a zinc metallopeptidase that consists of two homologous catalytic domains (known as nACE and cACE) with different substrate specificities. Based on kinetic studies it was previously reported sampatrilat, tight-binding inhibitor ACE, Ki = 13.8 nm 171.9 for cACE respectively [Sharma et al., Journal Chemical Information Modeling (2016), 56, 2486-2494], 12.4-fold more selective cACE. In addition, samAsp, in which an aspartate group replaces the sampatrilat lysine, found to be nonspecific lower micromolar affinity inhibitor. Here, we report detailed three-dimensional structural analysis samAsp binding ACE using high-resolution crystal structures elucidated by X-ray crystallography, provides molecular basis differences selectivity The show specificity can explained increased hydrophobic interactions H-bond from Glu403 lysine side chain are not observed nACE. clearly significantly greater number hydrophilic compared both consistent difference affinities. Our findings provide new experimental insights into ligand at active site pockets important design highly specific domain inhibitors ACE.The atomic coordinates structure factors N- C-domains bound sampatrilat-Asp complexes (6F9V, 6F9R, 6F9T 6F9U respectively) have been deposited Protein Data Bank, Research Collaboratory Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).