Structural highlights
Disease
[ECE1_HUMAN] Defects in ECE1 are a cause of Hirschsprung disease cardiac defects and autonomic dysfunction (HSCRCDAD) [MIM:613870]. It is a form of Hirschsprung disease with skip-lesions defects, craniofacial abnormalities and other dysmorphic features, and autonomic dysfunction.[1]
Function
[ECE1_HUMAN] Converts big endothelin-1 to endothelin-1.[2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Structure of human endothelin-converting enzyme I complexed with phosphoramidon.,Schulz H, Dale GE, Karimi-Nejad Y, Oefner C J Mol Biol. 2009 Jan 9;385(1):178-87. Epub 2008 Nov 1. PMID:18992253[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hofstra RM, Valdenaire O, Arch E, Osinga J, Kroes H, Loffler BM, Hamosh A, Meijers C, Buys CH. A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. Am J Hum Genet. 1999 Jan;64(1):304-8. PMID:9915973 doi:10.1086/302184
- ↑ Schweizer A, Valdenaire O, Nelbock P, Deuschle U, Dumas Milne Edwards JB, Stumpf JG, Loffler BM. Human endothelin-converting enzyme (ECE-1): three isoforms with distinct subcellular localizations. Biochem J. 1997 Dec 15;328 ( Pt 3):871-7. PMID:9396733
- ↑ 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. Epub 2008 Nov 1. PMID:18992253 doi:10.1016/j.jmb.2008.10.052
