7PQN の概要
| エントリーDOI | 10.2210/pdb7pqn/pdb |
| 分子名称 | Ecotin, Mannan-binding lectin serine protease 2 A chain, Mannan-binding lectin serine protease 2 B chain, ... (5 entities in total) |
| 機能のキーワード | serine protease, complement, inhibitor, immune system |
| 由来する生物種 | Escherichia coli (strain K12) 詳細 |
| タンパク質・核酸の鎖数 | 6 |
| 化学式量合計 | 108253.01 |
| 構造登録者 | |
| 主引用文献 | Nagy, Z.A.,Heja, D.,Bencze, D.,Kiss, B.,Boros, E.,Szakacs, D.,Fodor, K.,Wilmanns, M.,Kocsis, A.,Dobo, J.,Gal, P.,Harmat, V.,Pal, G. Synergy of protease-binding sites within the ecotin homodimer is crucial for inhibition of MASP enzymes and for blocking lectin pathway activation. J.Biol.Chem., 298:101985-101985, 2022 Cited by PubMed Abstract: Ecotin is a homodimeric serine protease inhibitor produced by many commensal and pathogenic microbes. It functions as a virulence factor, enabling survival of various pathogens in the blood. The ecotin dimer binds two protease molecules, and each ecotin protomer has two protease-binding sites: site1 occupies the substrate-binding groove, whereas site2 engages a distinct secondary region. Owing to the twofold rotational symmetry within the ecotin dimer, sites 1 and 2 of a protomer bind to different protease molecules within the tetrameric complex. Escherichia coli ecotin inhibits trypsin-like, chymotrypsin-like, and elastase-like enzymes, including pancreatic proteases, leukocyte elastase, key enzymes of blood coagulation, the contact and complement systems, and other antimicrobial cascades. Here, we show that mannan-binding lectin-associated serine protease-1 (MASP-1) and MASP-2, essential activators of the complement lectin pathway, and MASP-3, an essential alternative pathway activator, are all inhibited by ecotin. We decipher in detail how the preorganization of site1 and site2 within the ecotin dimer contributes to the inhibition of each MASP enzyme. In addition, using mutated and monomeric ecotin variants, we show that site1, site2, and dimerization contribute to inhibition in a surprisingly target-dependent manner. We present the first ecotin:MASP-1 and ecotin:MASP-2 crystal structures, which provide additional insights and permit structural interpretation of the observed functional results. Importantly, we reveal that monomerization completely disables the MASP-2-inhibitory, MASP-3-inhibitory, and lectin pathway-inhibitory capacity of ecotin. These findings provide new opportunities to combat dangerous multidrug-resistant pathogens through development of compounds capable of blocking ecotin dimer formation. PubMed: 35483450DOI: 10.1016/j.jbc.2022.101985 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (2.40001520992 Å) |
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