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 language | English |
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Pages (from-to) | 327-336 |
Number of pages | 10 |
Journal | FEBS Letters |
Volume | 594 |
Issue number | 2 |
Early online date | 12 Sept 2019 |
DOIs | |
Publication status | Published - 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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