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

Gyles E Cozier, Sylva L Schwager, Rajni K Sharma, Kelly Chibale, Edward D Sturrock, K Ravi Acharya

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)1477-1490
Number of pages14
JournalFEBS Journal
Volume285
Issue number8
Early online date24 Feb 2018
DOIs
Publication statusPublished - 1 Apr 2018

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Peptidyl-Dipeptidase A
Hydrophobic and Hydrophilic Interactions
Angiotensin-Converting Enzyme Inhibitors
Lysine
Catalytic Domain
X Ray Crystallography
Metalloproteases
Substrate Specificity
Aspartic Acid
sampatrilat
Zinc
Ligands

Keywords

  • angiotensin-1-converting enzyme
  • crystallography
  • domain specificity
  • enzyme kinetics
  • enzyme structure
  • metalloprotease
  • sampatrilat

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE : a molecular basis for domain-selectivity. / Cozier, Gyles E; Schwager, Sylva L; Sharma, Rajni K; Chibale, Kelly; Sturrock, Edward D; Acharya, K Ravi.

In: FEBS Journal, Vol. 285, No. 8, 01.04.2018, p. 1477-1490.

Research output: Contribution to journalArticle

Cozier, Gyles E ; Schwager, Sylva L ; Sharma, Rajni K ; Chibale, Kelly ; Sturrock, Edward D ; Acharya, K Ravi. / Crystal structures of sampatrilat and sampatrilat-Asp in complex with human ACE : a molecular basis for domain-selectivity. In: FEBS Journal. 2018 ; Vol. 285, No. 8. pp. 1477-1490.
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AU - Chibale, Kelly

AU - Sturrock, Edward D

AU - Acharya, K Ravi

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