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

The FEBS Journal
Gyles E CozierK R Acharya

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 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 s...Continue Reading

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Citations

May 16, 2019·Medicinal Chemistry·Mája Polakovičová, Josef Jampílek
Feb 6, 2020·International Journal of Molecular Sciences·Yara ChamataPaula Jauregi
Mar 21, 2020·The Biochemical Journal·Gyles E CozierK Ravi Acharya
Jan 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Julio Caballero
Mar 17, 2020·Pharmacology & Therapeutics·Marcos V PeriniAshwini L Chand
Oct 30, 2018·Journal of Medicinal Chemistry·Gyles E CozierK Ravi Acharya

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Methods Mentioned

BETA
X‐ray

Software Mentioned

DIALS
Ligplot +
CCP4
nACE
Phenix
PHASER
AIMLESS
REFMAC5
samAsp
cACE

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