7uac | pdb_00007uac
Human pro-meprin alpha (zymogen state)
Structural highlights
FunctionPublication Abstract from PubMedThe zinc-dependent metalloprotease meprin alpha 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 alpha performs key roles in inflammation, immunity, and extracellular matrix remodelling. Dysregulated meprin alpha is associated with acute kidney injury, sepsis, urinary tract infection, metastatic colorectal carcinoma, and inflammatory bowel disease. Accordingly, meprin alpha is the target of drug discovery programs. In contrast to meprin beta, meprin alpha 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 alpha, 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 alpha 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 beta reveal unique features of the active site of meprin alpha, and helical assembly more broadly. Helical ultrastructure of the metalloprotease meprin alpha in complex with a small molecule inhibitor.,Bayly-Jones C, Lupton CJ, Fritz C, Venugopal H, Ramsbeck D, Wermann M, Jager C, de Marco A, Schilling S, Schlenzig D, Whisstock JC Nat Commun. 2022 Oct 19;13(1):6178. doi: 10.1038/s41467-022-33893-7. PMID:36261433[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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