4DJZ

Catalytic fragment of masp-1 in complex with its specific inhibitor developed by directed evolution on sgci scaffold

Summary for 4DJZ

• Entry DOI: 10.2210/pdb4djz/pdb
• Related: 3TVJ
• Descriptor: Mannan-binding lectin serine protease 1 heavy chain, Mannan-binding lectin serine protease 1 light chain, Protease inhibitor SGPI-2, ... (4 entities in total)
• Functional Keywords: in vitro evolution, specific inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P48740 P48740 O46162
• Total number of polymer chains: 6
• Total formula weight: 99251.53

Authors

Heja, D.,Harmat, V.,Fodor, K.,Wilmanns, M.,Dobo, J.,Kekesi, K.A.,Zavodszky, P.,Gal, P.,Pal, G. (deposition date: 2012-02-03, release date: 2012-04-25, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.2 Å)