Key result
A three-dimensional model of the endothelin-converting enzyme 1 ectodomain was constructed using human NEP as a template to facilitate the discovery of novel inhibitors.
The development of a 3D structural model of ECE-1 provides a foundation for designing novel inhibitors for conditions such as hypertension.
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May aid ECE-1 inhibitor design for hypertension; leaves open clinical translation from this preclinical model.
Endothelin-converting enzyme 1 (ECE-1, EC 3.4.24.71) is a zinc-dependent type II mammalian membrane protein comprising the active site in the ectodomain. It exists in multiple splice variants that all catalyze the last and rate-limiting step in the activation of preproendothelin to the highly potent vasoconstrictor endothelin. There is high interest in finding small and potent inhibitors for this enzyme that could be used in numerous indications, e.g. hypertension. Since there is no structural information available for this important enzyme, we built a model of the complete ectodomain using the recently solved structure of human NEP as template. The naturally derived metalloproteinase inhibitor phosphoramidon was docked in the active site of this model and comparisons with the respective NEP complex were made.
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Bur et al. (2001) studied this question. Three-dimensional modeling and molecular docking was evaluated. A three-dimensional model of the endothelin-converting enzyme 1 ectodomain was constructed using human NEP as a template to facilitate the discovery of novel inhibitors.
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