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. 2020 Jan;594(2):327-336.
doi: 10.1002/1873-3468.13602. Epub 2019 Sep 21.

Crystal structure of peptide-bound neprilysin reveals key binding interactions

Stephen Moss  1 , Vasanta Subramanian  1 , K Ravi Acharya  1
Affiliations
Free article

Crystal structure of peptide-bound neprilysin reveals key binding interactions

Stephen Moss et al. FEBS Lett. 2020 Jan.
Free article

Abstract

Neprilysin (NEP) is a promiscuous zinc metalloprotease with broad substrate specificity and cleaves a remarkable diversity of substrates through endopeptidase action. Two of these - amyloid-β 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 Å 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.

Keywords: NEP; crystallography; neprilysin; neutral endopeptidase; peptide-bound; protein structure; zinc metalloprotease.

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