German Federal Ministry for Education and Research
ドイツ
Australian Research Council (ARC)
オーストラリア
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor. 著者: Charles Bayly-Jones / Christopher J Lupton / Claudia Fritz / Hariprasad Venugopal / Daniel Ramsbeck / Michael Wermann / Christian Jäger / Alex de Marco / Stephan Schilling / Dagmar Schlenzig ...著者: Charles Bayly-Jones / Christopher J Lupton / Claudia Fritz / Hariprasad Venugopal / Daniel Ramsbeck / Michael Wermann / Christian Jäger / Alex de Marco / Stephan Schilling / Dagmar Schlenzig / James C Whisstock / 要旨: 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 ...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.
全体 : Single subunit of helical meprin alpha in the zymogen state
全体
名称: Single subunit of helical meprin alpha in the zymogen state
要素
複合体: Single subunit of helical meprin alpha in the zymogen state
タンパク質・ペプチド: Meprin A subunit alphaメプリンA
リガンド: CALCIUM IONカルシウム
リガンド: ZINC ION
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超分子 #1: Single subunit of helical meprin alpha in the zymogen state
超分子
名称: Single subunit of helical meprin alpha in the zymogen state タイプ: complex / キメラ: Yes / ID: 1 / 親要素: 0 / 含まれる分子: #1 詳細: Focused classification and local refinement reconstruction of single subunit of recombinant, secreted helical pro-meprin alpha