8eok

Structure of the C3bB proconvertase in complex with lufaxin and factor Xa

spinqualitylabelsall models 8eok, resolution 3.53Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8eok is a 6 chain structure with sequence from Homo sapiens and Lutzomyia longipalpis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.53Å Ligands: BMA, MG, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LUFX_LUTLO Sand fly salivary protein with antithrombotic, and anti-complement (alternative pathway) activities (PubMed:22796577, PubMed:28912782). Is a slow, tight, non-competitive, and reversible inhibitor of factor Xa (FXa, F10) (PubMed:22796577). Is specific for FXa (Kd=3.86 nM) and does not interact with non-activated FX, or all other enzymes tested (PubMed:22796577). In addition, it blocks prothrombinase and increases both prothrombin time and activated partial thromboplastin time (PubMed:22796577). It also prevents protease-activated receptor 2 (F2RL1, PAR2) activation by FXa (PubMed:22796577). In vivo, it abrogates edema formation triggered by injection of FXa in the paw of mice (PubMed:22796577). Moreover, it prevents FeCl3-induced carotid artery thrombus formation and prolongs activated partial thromboplastin time ex vivo, implying that it works as an anticoagulant in vivo (PubMed:22796577). It also inhibits the early steps of the alternative pathway of complement by direct binding to the proconvertase C3b-B complex, by inhibiting activation of factor B and consequently the formation of the C3 convertase (PubMed:28912782). Publication Abstract from PubMed 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 beta-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. A bispecific inhibitor of complement and coagulation blocks activation in complementopathy models via a novel mechanism.,Andersen JF, Lei H, Strayer EC, Kanai T, Pham V, Pan XZ, Alvarenga PH, Gerber GF, Asojo OA, Francischetti IMB, Brodsky RA, Valenzuela JG, Ribeiro JMC Blood. 2023 Jun 22;141(25):3109-3121. doi: 10.1182/blood.2022019359. PMID:36947859 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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