Crystal structure of peptide-bound neprilysin reveals key binding interactions

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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.

Original languageEnglish
Pages (from-to)327-336
Number of pages10
JournalFEBS Letters
Issue number2
Early online date12 Sept 2019
Publication statusPublished - 29 Feb 2020

Bibliographical note

© 2019 Federation of European Biochemical Societies.


  • crystallography
  • NEP
  • neprilysin
  • neutral endopeptidase
  • peptide-bound
  • protein structure
  • zinc metalloprotease

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology


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