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| | ==Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model== | | ==Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model== |
| - | <StructureSection load='4dtg' size='340' side='right' caption='[[4dtg]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4dtg' size='340' side='right'caption='[[4dtg]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4dtg]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DTG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DTG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4dtg]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DTG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DTG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tfx|1tfx]], [[1adz|1adz]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LACI, TFPI, TFPI (AMINO ACIDS 119-178), TFPI1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4dtg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dtg OCA], [https://pdbe.org/4dtg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dtg RCSB], [https://www.ebi.ac.uk/pdbsum/4dtg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dtg ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dtg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dtg OCA], [http://pdbe.org/4dtg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dtg RCSB], [http://www.ebi.ac.uk/pdbsum/4dtg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dtg ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TFPI1_HUMAN TFPI1_HUMAN]] Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma. | + | [https://www.uniprot.org/uniprot/TFPI1_HUMAN TFPI1_HUMAN] Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| | + | *[[Antibody 3D structures|Antibody 3D structures]] |
| | + | *[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]] |
| | *[[Tissue factor pathway inhibitor|Tissue factor pathway inhibitor]] | | *[[Tissue factor pathway inhibitor|Tissue factor pathway inhibitor]] |
| - | *[[3D structures of antibody|3D structures of antibody]] | + | *[[3D structures of human antibody|3D structures of human antibody]] |
| - | *[[3D structures of monoclonal antibody|3D structures of monoclonal antibody]]
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Breinholt, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Hilden, I]] | + | [[Category: Breinholt J]] |
| - | [[Category: Krogh, B O]] | + | [[Category: Hilden I]] |
| - | [[Category: Svensson, L A]] | + | [[Category: Krogh BO]] |
| - | [[Category: Antibody]] | + | [[Category: Svensson LA]] |
| - | [[Category: Blood clotting inhibitor-immune system complex]]
| + | |
| - | [[Category: Blood coagulation]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| Structural highlights
Function
TFPI1_HUMAN Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma.
Publication Abstract from PubMed
Hemophilia is treated by intravenous replacement therapy with factor VIII (FVIII) or factor IX (FIX), either on demand to resolve bleeding, or as prophylaxis. Improved treatment may be provided by drugs designed for subcutaneous and less frequent administration with a reduced risk of inhibitor formation. Tissue factor pathway inhibitor (TFPI) down regulates the initiation of coagulation by inhibition of FVIIa/TF/FXa. Blockage of TFPI inhibition may facilitate thrombin generation in a hemophilic setting. A high-affinity (K(D) = 25 pM) monoclonal antibody, mAb 2021, against TFPI was investigated. Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa and improved clot formation in hemophilia blood and plasma. The binding epitope on Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extensive overlap with the FXa contact region highlighting a structural basis for its mechanism of action. In a rabbit hemophilia model, intravenous or subcutaneous dose significantly reduced cuticle bleeding. mAb 2021 showed effect comparable to that of rFVIIa. Cuticle bleeding in the model was reduced for at least 7 days by a single intravenous dose of mAb 2021. This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option in hemophilia.
Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model.,Hilden I, Lauritzen B, Sorensen BB, Clausen JT, Jespersgaard C, Krogh BO, Bowler AN, Breinholt J, Gruhler A, Svensson LA, Petersen HH, Petersen LC, Balling KW, Hansen L, Hermit MB, Egebjerg T, Friederichsen B, Ezban M, Bjorn SE Blood. 2012 May 4. PMID:22563084[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hilden I, Lauritzen B, Sorensen BB, Clausen JT, Jespersgaard C, Krogh BO, Bowler AN, Breinholt J, Gruhler A, Svensson LA, Petersen HH, Petersen LC, Balling KW, Hansen L, Hermit MB, Egebjerg T, Friederichsen B, Ezban M, Bjorn SE. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood. 2012 May 4. PMID:22563084 doi:10.1182/blood-2012-01-401620
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