7UAE

Human meprin alpha (active state)

7UAE の概要

• エントリーDOI: 10.2210/pdb7uae/pdb
• EMDBエントリー: 26419 26420 26421 26422 26423 26424 26426
• 分子名称: Meprin A subunit alpha, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: metalloprotease, complex, helical, extracellular, oncoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 70407.16

構造登録者

Bayly-Jones, C.,Lupton, C.J.,Fritz, C.,Schlenzig, D.,Whisstock, J.C. (登録日: 2022-03-12, 公開日: 2022-11-02, 最終更新日: 2024-10-30)

主引用文献

Bayly-Jones, C.,Lupton, C.J.,Fritz, C.,Venugopal, H.,Ramsbeck, D.,Wermann, M.,Jager, C.,de Marco, A.,Schilling, S.,Schlenzig, D.,Whisstock, J.C.
Helical ultrastructure of the metalloprotease meprin alpha in complex with a small molecule inhibitor.
Nat Commun, 13:6178-6178, 2022

PubMed 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.

PubMed: 36261433
DOI: 10.1038/s41467-022-33893-7

実験手法

ELECTRON MICROSCOPY (2.6 Å)