title: Structure of human endothelin-converting enzyme I complexed with phosphoramidon.
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.
authors.affiliation: Morphochem AG, Basel Switzerland.
authors.forename: Henk
authors.initials: H
authors.lastname: Schulz
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Dale
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Karimi-Nejad
authors.forename: Christian
authors.initials: C
authors.lastname: Oefner
mesh_terms: D000595:Amino Acid Sequence; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006020:Glycopeptides / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000737:chemistry; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013379:Substrate Specificity / Q000187:drug effects; D013499:Surface Properties / Q000187:drug effects; D015032:Zinc / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006020:Glycopeptides; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes; D015032:Zinc; C008890:phosphoramidon