- EMDB-28378: Structure of the C3bB proconvertase in complex with lufaxin and f... -
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基本情報
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データベース: EMDB / ID: EMD-28378
タイトル
Structure of the C3bB proconvertase in complex with lufaxin and factor Xa
マップデータ
試料
複合体: The C3 proconvertase from the alternative pathway of complement in complex with lufaxin, a complement/coagulation inhibitor and coagulation factor Xa
タンパク質・ペプチド: Complement C3 beta chain
タンパク質・ペプチド: Complement C3b alpha' chain
タンパク質・ペプチド: Complement factor B
タンパク質・ペプチド: Factor X light chain
タンパク質・ペプチド: Activated factor Xa heavy chain
タンパク質・ペプチド: Lufaxin
リガンド: MAGNESIUM ION
リガンド: 2-acetamido-2-deoxy-beta-D-glucopyranose
キーワード
Complement / Alternative pathway / inhibitor / sand fly / IMMUNE SYSTEM
機能・相同性
機能・相同性情報
alternative-complement-pathway C3/C5 convertase / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / complement binding / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation ...alternative-complement-pathway C3/C5 convertase / C5L2 anaphylatoxin chemotactic receptor binding / oviduct epithelium development / regulation of triglyceride biosynthetic process / complement binding / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation / coagulation factor Xa / Activation of C3 and C5 / positive regulation of phagocytosis, engulfment / positive regulation of lipid storage / positive regulation of G protein-coupled receptor signaling pathway / positive regulation of type IIa hypersensitivity / complement receptor mediated signaling pathway / Defective factor IX causes thrombophilia / Defective cofactor function of FVIIIa variant / Defective F9 variant does not activate FX / complement-dependent cytotoxicity / positive regulation of D-glucose transmembrane transport / complement activation / complement activation, alternative pathway / Extrinsic Pathway of Fibrin Clot Formation / endopeptidase inhibitor activity / neuron remodeling / amyloid-beta clearance / B cell activation / positive regulation of vascular endothelial growth factor production / positive regulation of TOR signaling / complement activation, classical pathway / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Purinergic signaling in leishmaniasis infection / Intrinsic Pathway of Fibrin Clot Formation / Peptide ligand-binding receptors / Regulation of Complement cascade / response to bacterium / Post-translational protein phosphorylation / fatty acid metabolic process / phospholipid binding / positive regulation of receptor-mediated endocytosis / Golgi lumen / positive regulation of protein phosphorylation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of angiogenesis / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / blood coagulation / azurophil granule lumen / toxin activity / blood microparticle / secretory granule lumen / G alpha (i) signalling events / immune response / positive regulation of cell migration / G protein-coupled receptor signaling pathway / inflammatory response / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / external side of plasma membrane / calcium ion binding / Neutrophil degranulation / cell surface / signal transduction / protein-containing complex / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane 類似検索 - 分子機能
Complement factor B / Complement B/C2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 ...Complement factor B / Complement B/C2 / Complement C3-like, NTR domain / : / : / Complement component 3, CUB domain, second segment / Complement component 3, CUB domain, first segment / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / Anaphylatoxin, complement system domain / : / Anaphylatoxin domain signature. / Alpha-macro-globulin thiol-ester bond-forming region / Anaphylatoxin, complement system / Anaphylatoxin/fibulin / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / Netrin C-terminal Domain / Netrin module, non-TIMP type / UNC-6/NTR/C345C module / Macroglobulin domain MG4 / Macroglobulin domain MG4 / Netrin domain / NTR domain profile. / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG3 / : / A-macroglobulin receptor binding domain / Macroglobulin domain MG3 / A-macroglobulin receptor / Tissue inhibitor of metalloproteinases-like, OB-fold / Alpha-2-macroglobulin / Macroglobulin domain / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Peptidase S1A, coagulation factor VII/IX/X/C/Z / Sushi repeat (SCR repeat) / : / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Coagulation factor-like, Gla domain superfamily / von Willebrand factor type A domain / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Coagulation Factor Xa inhibitory site / EGF-like domain / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / VWFA domain profile. / von Willebrand factor (vWF) type A domain / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / von Willebrand factor, type A / Epidermal growth factor-like domain. / von Willebrand factor A-like domain superfamily / EGF-like domain profile. / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Immunoglobulin-like fold / Peptidase S1, PA clan 類似検索 - ドメイン・相同性
Coagulation factor X / Complement factor B / Complement C3 / Lufaxin 類似検索 - 構成要素
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
米国
引用
ジャーナル: Blood / 年: 2023 タイトル: A bispecific inhibitor of complement and coagulation blocks activation in complementopathy models via a novel mechanism. 著者: John F Andersen / Haotian Lei / Ethan C Strayer / Tapan Kanai / Van Pham / Xiang-Zuo Pan / Patricia Hessab Alvarenga / Gloria F Gerber / Oluwatoyin A Asojo / Ivo M B Francischetti / Robert A ...著者: John F Andersen / Haotian Lei / Ethan C Strayer / Tapan Kanai / Van Pham / Xiang-Zuo Pan / Patricia Hessab Alvarenga / Gloria F Gerber / Oluwatoyin A Asojo / Ivo M B Francischetti / Robert A Brodsky / Jesus G Valenzuela / José M C Ribeiro / 要旨: Inhibitors of complement and coagulation are present in the saliva of a variety of blood-feeding arthropods that transmit parasitic and viral pathogens. Here, we describe the structure and mechanism ...Inhibitors of complement and coagulation are present in the saliva of a variety of blood-feeding arthropods that transmit parasitic and viral pathogens. Here, we describe the structure and mechanism of action of the sand fly salivary protein lufaxin, which inhibits the formation of the central alternative C3 convertase (C3bBb) and inhibits coagulation factor Xa (fXa). Surface plasmon resonance experiments show that lufaxin stabilizes the binding of serine protease factor B (FB) to C3b but does not detectably bind either C3b or FB alone. The crystal structure of the inhibitor reveals a novel all β-sheet fold containing 2 domains. A structure of the lufaxin-C3bB complex obtained via cryo-electron microscopy (EM) shows that lufaxin binds via its N-terminal domain at an interface containing elements of both C3b and FB. By occupying this spot, the inhibitor locks FB into a closed conformation in which proteolytic activation of FB by FD cannot occur. C3bB-bound lufaxin binds fXa at a separate site in its C-terminal domain. In the cryo-EM structure of a C3bB-lufaxin-fXa complex, the inhibitor binds to both targets simultaneously, and lufaxin inhibits fXa through substrate-like binding of a C-terminal peptide at the active site as well as other interactions in this region. Lufaxin inhibits complement activation in ex vivo models of atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH) as well as thrombin generation in plasma, providing a rationale for the development of a bispecific inhibitor to treat complement-related diseases in which thrombosis is a prominent manifestation.
全体 : The C3 proconvertase from the alternative pathway of complement i...
全体
名称: The C3 proconvertase from the alternative pathway of complement in complex with lufaxin, a complement/coagulation inhibitor and coagulation factor Xa
要素
複合体: The C3 proconvertase from the alternative pathway of complement in complex with lufaxin, a complement/coagulation inhibitor and coagulation factor Xa
タンパク質・ペプチド: Complement C3 beta chain
タンパク質・ペプチド: Complement C3b alpha' chain
タンパク質・ペプチド: Complement factor B
タンパク質・ペプチド: Factor X light chain
タンパク質・ペプチド: Activated factor Xa heavy chain
タンパク質・ペプチド: Lufaxin
リガンド: MAGNESIUM ION
リガンド: 2-acetamido-2-deoxy-beta-D-glucopyranose
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超分子 #1: The C3 proconvertase from the alternative pathway of complement i...
超分子
名称: The C3 proconvertase from the alternative pathway of complement in complex with lufaxin, a complement/coagulation inhibitor and coagulation factor Xa タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3, #5-#6