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Crystal structure of peptide‐bound neprilysin reveals key binding interactions

DOI: 10.1002/1873-3468.13602 DOI Help

Authors: Stephen Moss (University of Bath) , Vasanta Subramanian (University of Bath) , K. Ravi Acharya (University of Bath)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Febs Letters , VOL 46

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 17212

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.

Journal Keywords: crystallography; NEP; neprilysin; neutral endopeptidase; peptide‐bound; protein structure; zinc metalloprotease

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography

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