Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	A bispecific inhibitor of complement and coagulation blocks activation in complementopathy models via a novel mechanism.
Journal, issue, pages	Blood, Vol. 141, Issue 25, Page 3109-3121, Year 2023
Publish date	Jun 22, 2023
Authors	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 /
PubMed Abstract	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.
External links	Blood / PubMed:36947859 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	2.31 - 3.53 Å
Structure data	28279 8enu EMDB-28279, PDB-8enu: Structure of the C3bB proconvertase in complex with lufaxin Method: EM (single particle) / Resolution: 3.22 Å 28378 8eok EMDB-28378, PDB-8eok: Structure of the C3bB proconvertase in complex with lufaxin and factor Xa Method: EM (single particle) / Resolution: 3.53 Å PDB-8eo2: Lufaxin a bifunctional inhibitor of complement and coagulation Method: X-RAY DIFFRACTION / Resolution: 2.31 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine ChemComp-GOL: GLYCEROL / Glycerol ChemComp-BR: BROMIDE ION / Bromide ChemComp-HOH: WATER / Water ChemComp-MG: Unknown entry
Source	homo sapiens (human) lutzomyia longipalpis (insect)
Keywords	IMMUNE SYSTEM / Complement / Alternative pathway / inhibitor / sand fly / BLOOD CLOTTING / coagulation / salivary