8eok
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 8eok is ON HOLD Authors: Andersen, J.F., Lei, H. Description: Structure of the C3bB proconvertase in complex with lufaxin and factor Xa [[Category:...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of the C3bB proconvertase in complex with lufaxin and factor Xa== | |
| + | <StructureSection load='8eok' size='340' side='right'caption='[[8eok]], [[Resolution|resolution]] 3.53Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8eok]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lutzomyia_longipalpis Lutzomyia longipalpis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8EOK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EOK FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.53Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8eok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8eok OCA], [https://pdbe.org/8eok PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8eok RCSB], [https://www.ebi.ac.uk/pdbsum/8eok PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8eok ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/LUFX_LUTLO 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).<ref>PMID:22796577</ref> <ref>PMID:28912782</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:36947859</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Andersen | + | <div class="pdbe-citations 8eok" style="background-color:#fffaf0;"></div> |
| - | [[Category: Lei | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Lutzomyia longipalpis]] | ||
| + | [[Category: Andersen JF]] | ||
| + | [[Category: Lei H]] | ||
Current revision
Structure of the C3bB proconvertase in complex with lufaxin and factor Xa
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