Structure of human endothelin-converting enzyme I complexed with phosphoramidon.
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Schulz H, Dale GE, Karimi-Nejad Y, Oefner C
Structure of human endothelin-converting enzyme I complexed with phosphoramidon.
J Mol Biol. 2009 Jan 9;385(1):178-87. doi: 10.1016/j.jmb.2008.10.052. Epub 2008 Nov 1.
- PubMed ID
- 18992253 [ View in PubMed]
- Abstract
Endothelin-converting enzyme I (ECE-1) is a mammalian type II integral membrane zinc-containing endopeptidase. ECE-1 catalyzes the final step in the biosynthesis of endothelins in a rate-limiting fashion, through post-translational conversion of the biologically inactive big endothelins. Endothelin-1 overproduction has been implicated in a heterogeneous list of diseases including systemic and pulmonary hypertension, stroke and asthma, cardiac and renal failure. Therefore, ECE-1 is a prime therapeutic target for the regulation of endothelin-1 production in vivo and there is considerable interest in selective inhibitors of this enzyme. Here, we present the crystal structure of the extracellular domain (residues 90-770) of human ECE-1 (C428S) with the generic metalloprotease inhibitor phosphoramidon determined at 2.38 A resolution. The structure is closely related to that of human NEP, providing essential information for a detailed understanding of ligand-binding, specificity determinants as well as selectivity criteria. Selective inhibitors of ECE-1s should have beneficial effects for the treatment of diseases in which an overproduction of ETs plays a pathogenic role.