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| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8tqs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tqs OCA], [https://pdbe.org/8tqs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tqs RCSB], [https://www.ebi.ac.uk/pdbsum/8tqs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tqs ProSAT]</span></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=8tqs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tqs OCA], [https://pdbe.org/8tqs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tqs RCSB], [https://www.ebi.ac.uk/pdbsum/8tqs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tqs ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | + | <div style="background-color:#fffaf0;"> |
| - | [https://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN] Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:[https://omim.org/entry/613679 613679]. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels.<ref>PMID:14962227</ref> <ref>PMID:6405779</ref> <ref>PMID:3771562</ref> <ref>PMID:3567158</ref> <ref>PMID:3801671</ref> <ref>PMID:3242619</ref> <ref>PMID:2719946</ref> <ref>PMID:1354985</ref> <ref>PMID:1421398</ref> <ref>PMID:1349838</ref> <ref>PMID:7865694</ref> <ref>PMID:7792730</ref> Genetic variations in F2 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:[https://omim.org/entry/601367 601367]; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors.<ref>PMID:15534175</ref> Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:[https://omim.org/entry/188050 188050]. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:[https://omim.org/entry/614390 614390]. A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions.<ref>PMID:11506076</ref>
| + | == Publication Abstract from PubMed == |
| - | == Function ==
| + | Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor's selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications. |
| - | [https://www.uniprot.org/uniprot/THRB_HUMAN THRB_HUMAN] Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing.<ref>PMID:2856554</ref>
| + | |
| | + | Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.,Yu H, Kumar S, Frederiksen JW, Kolyadko VN, Pitoc G, Layzer J, Yan A, Rempel R, Francis S, Krishnaswamy S, Sullenger BA Nat Commun. 2024 May 10;15(1):3977. doi: 10.1038/s41467-024-48211-6. PMID:38730234<ref>PMID:38730234</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 8tqs" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Structural highlights
8tqs is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.207Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Publication Abstract from PubMed
Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor's selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.
Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.,Yu H, Kumar S, Frederiksen JW, Kolyadko VN, Pitoc G, Layzer J, Yan A, Rempel R, Francis S, Krishnaswamy S, Sullenger BA Nat Commun. 2024 May 10;15(1):3977. doi: 10.1038/s41467-024-48211-6. PMID:38730234[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yu H, Kumar S, Frederiksen JW, Kolyadko VN, Pitoc G, Layzer J, Yan A, Rempel R, Francis S, Krishnaswamy S, Sullenger BA. Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors. Nat Commun. 2024 May 10;15(1):3977. PMID:38730234 doi:10.1038/s41467-024-48211-6
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