3TVJ

Catalytic fragment of MASP-2 in complex with its specific inhibitor developed by directed evolution on SGCI scaffold

3TVJ の概要

• エントリーDOI: 10.2210/pdb3tvj/pdb
• 関連するPDBエントリー: 4DJZ
• 分子名称: Mannan-binding lectin serine protease 2 A chain, Mannan-binding lectin serine protease 2 B chain, Protease inhibitor SGPI-2, ... (5 entities in total)
• 機能のキーワード: in vitro evolution, specific inhibitor, allostery, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: O00187 O00187 O46162
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 39876.91

構造登録者

Heja, D.,Harmat, V.,Dobo, J.,Szasz, R.,Kekesi, K.A.,Zavodszky, P.,Gal, P.,Pal, G. (登録日: 2011-09-20, 公開日: 2012-04-25, 最終更新日: 2024-11-20)

主引用文献

Heja, D.,Harmat, V.,Fodor, K.,Wilmanns, M.,Dobo, J.,Kekesi, K.A.,Zavodszky, P.,Gal, P.,Pal, G.
Monospecific Inhibitors Show That Both Mannan-binding Lectin-associated Serine Protease-1 (MASP-1) and -2 Are Essential for Lectin Pathway Activation and Reveal Structural Plasticity of MASP-2.
J.Biol.Chem., 287:20290-20300, 2012

PubMed Abstract: The lectin pathway is an antibody-independent activation route of the complement system. It provides immediate defense against pathogens and altered self-cells, but it also causes severe tissue damage after stroke, heart attack, and other ischemia reperfusion injuries. The pathway is triggered by target binding of pattern recognition molecules leading to the activation of zymogen mannan-binding lectin-associated serine proteases (MASPs). MASP-2 is considered as the autonomous pathway-activator, while MASP-1 is considered as an auxiliary component. We evolved a pair of monospecific MASP inhibitors. In accordance with the key role of MASP-2, the MASP-2 inhibitor completely blocks the lectin pathway activation. Importantly, the MASP-1 inhibitor does the same, demonstrating that MASP-1 is not an auxiliary but an essential pathway component. We report the first Michaelis-like complex structures of MASP-1 and MASP-2 formed with substrate-like inhibitors. The 1.28 Å resolution MASP-2 structure reveals significant plasticity of the protease, suggesting that either an induced fit or a conformational selection mechanism should contribute to the extreme specificity of the enzyme.

PubMed: 22511776
DOI: 10.1074/jbc.M112.354332

実験手法

X-RAY DIFFRACTION (1.28 Å)