Crystal structure of peptide-bound neprilysin reveals key binding interactions

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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.

Original languageEnglish
Pages (from-to)327-336
Number of pages10
JournalFEBS Letters
Volume594
Issue number2
Early online date12 Sept 2019
DOIs
Publication statusPublished - 29 Feb 2020

Bibliographical note

© 2019 Federation of European Biochemical Societies.

Funding

We thank Diamond Light Source for access to beamline I04 (proposal mx17212) that resulted in the presentation of data here. SM is supported by a postgraduate studentship from the Alzheimer’s Society (UK) awarded to KRA and VS [grant number –286 (AS‐PhD2015b‐006)].

Keywords

  • 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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