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 |
|---|---|
| Pages (from-to) | 327-336 |
| Number of pages | 10 |
| Journal | FEBS Letters |
| Volume | 594 |
| Issue number | 2 |
| Early online date | 12 Sep 2019 |
| DOIs | |
| Publication status | Published - 29 Feb 2020 |
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
Access to Document
- FEBSL-19-0870.R2_Proof_hi
This is the peer reviewed version of the following article: Moss, S., Subramanian, V., & Acharya, K. R. (2019). Crystal structure of peptide-bound neprilysin reveals key binding interactions. FEBS Letters, which has been published in final form at https://doi.org/10.1002/1873-3468.13602. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.