6sh1
Crystal structure of substrate-free human neprilysin E584D.
Structural highlights
FunctionNEP_HUMAN Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.[1] [2] [3] Publication Abstract from PubMedNeprilysin (NEP) is a promiscuous zinc metalloprotease with broad substrate specificity and cleaves a remarkable diversity of substrates through endopeptidase action. Two of these - amyloid-beta and natriuretic peptides - implicate the enzyme in both Alzheimer's disease and cardiovascular disease, respectively. Here, we report the creation of a catalytically inactive NEP (E584D) to determine the first peptide-bound crystal structure at 2.6 A resolution. The structure reveals key interactions involved in substrate binding which we have identified to be conserved in other known zinc metalloproteases. In addition, the structure provides evidence for a potential exosite within the central cavity that may play a critical role in substrate positioning. Together, these results contribute to our understanding of the molecular function of NEP. Crystal structure of peptide-bound neprilysin reveals key binding interactions.,Moss S, Subramanian V, Acharya KR FEBS Lett. 2020 Jan;594(2):327-336. doi: 10.1002/1873-3468.13602. Epub 2019 Sep, 21. PMID:31514225[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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