ArticleNature communications2022
Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 12 citations in OpenAlex.
- Knowledge-driven interpretable neural networks provide mechanistic insight.Genome research · 2026Article
- Serum meprin α levels for the detection of systemic inflammatory response syndrome.Molecular medicine (Cambridge, Mass.) · 2026Article
- The Role of Meprins on the Brain Extracellular Matrix and Perineuronal Nets.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Ageing impacts extracellular matrix turnover and remodelling in the kidney.Matrix biology plus · 2026Article
- Article
- Exploring cadmium-binding proteins in Japanese scallops Mizuhopecten yessoensis: isolation and characterization.Environmental science and pollution research international · 2025Article
- Preventive effect of small molecule active substances on septic cardiomyopathy after abdominal trauma: a systematic review and meta-analysis.Frontiers in pharmacology · 2025Article
- Astacin metalloproteases in human-parasitic nematodes.Advances in parasitology · 2024Review
- Cryo-EM structure of influenza helical nucleocapsid reveals NP-NP and NP-RNA interactions as a model for the genome encapsidation.Science advances · 2023Article
- Synthesis and structure-activity relationships of pyrazole-based inhibitors of meprin α and β.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Proteolytic processing of galectin-3 by meprin metalloproteases is crucial for host-microbiome homeostasis.Science advances · 2023Article
- Structural and evolutionary insights into astacin metallopeptidases.Frontiers in molecular biosciences · 2022Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin α performs key roles in inflammation, immunity, and extracellular matrix remodelling. Dysregulated meprin α is associated with acute kidney injury, sepsis, urinary tract infection, metastatic colorectal carcinoma, and inflammatory bowel disease. Accordingly, meprin α is the target of drug discovery programs. In contrast to meprin β, meprin α is secreted into the extracellular space, whereupon it oligomerises to form giant assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin α, as well as the structure of the active form in complex with a prototype small molecule inhibitor and human fetuin-B. Our data reveal that meprin α forms a giant, flexible, left-handed helical assembly of roughly 22 nm in diameter. We find that oligomerisation improves proteolytic and thermal stability but does not impact substrate specificity or enzymatic activity. Furthermore, structural comparison with meprin β reveal unique features of the active site of meprin α, and helical assembly more broadly.
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