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

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, Ki=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 non-specific 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. This article is protected by copyright. All rights reserved.

LanguageEnglish
JournalFEBS Journal
Early online date24 Feb 2018
DOIs
StatusE-pub ahead of print - 24 Feb 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

  • Journal Article

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, 24.02.2018.

Research output: Contribution to journalArticle

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AU - Schwager, Sylva L

AU - Sharma, Rajni K

AU - Chibale, Kelly

AU - Sturrock, Edward D

AU - Acharya, K Ravi

N1 - This article is protected by copyright. All rights reserved.

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N2 - 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, Ki=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 non-specific 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. This article is protected by copyright. All rights reserved.

AB - 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, Ki=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 non-specific 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. This article is protected by copyright. All rights reserved.

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