| http://purl.uniprot.org/citations/18000606 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/18000606 | http://www.w3.org/2000/01/rdf-schema#comment | "Natural inhibitors of coagulation or inflammation such as the serpins antithrombin (AT), heparin cofactor II (HCII), and alpha(1)-proteinase inhibitor (alpha(1)-PI) can be overwhelmed in thrombosis and/or sepsis. The reactive centre (P1-P1') variant alpha(1)-PI M358R inhibits not only procoagulant thrombin but also anticoagulant activated protein C (APC). We previously described HAPI M358R, comprising a fusion of HCII residues 1-75 to the N-terminus of a(1)-PI M358R that yielded increased anti-thrombin, but not anti-APC activity. We hypothesized that further alterations to the HAPI M358R reactive centre loop would yield additional refinements in specificity. The reactions with thrombin or APC of recombinant alpha(1)-PI M358R variants with or without the HCII extension were characterized electrophoretically and kinetically. Their extension of clotting times and inhibition of fibrin-bound thrombin were measured, and the survival of HAPI M358R in mice was determined. Replacing the P7-P3 and P2' residues of HAPI M358R with AT residues reduced APC inhibition rates by 140-fold, but those of thrombin less than two-fold;substituting the P16-P2 and P2'-P3' residues of HAPI M358R with HCII residues reduced APC inhibition rates by 180-fold, but those of thrombin 10.5-fold. Fused variants extended thrombin clotting times more effectively than unfused inhibitors, were at least as effective at inhibiting clot-bound thrombin, and remained intact in the murine circulation. The combination of modifications inside and outside the RCL resulted in a 1,360-fold increase in selectivity of HAPI M358R (AT P7-P3/P2') for thrombin versus APC relative to alpha(1)-PI M358R. Our results predict that this protein may be effective in limiting thrombosis in vivo."xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.org/dc/terms/identifier | "doi:10.1160/th07-03-0197"xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/author | "Bhakta V."xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/author | "Sheffield W.P."xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/author | "Sutherland J.S."xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/date | "2007"xsd:gYear |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/name | "Thromb Haemost"xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/pages | "1014-1023"xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/title | "The appended tail region of heparin cofactor II and additional reactive centre loop mutations combine to increase the reactivity and specificity of alpha1-proteinase inhibitor M358R for thrombin."xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://purl.uniprot.org/core/volume | "98"xsd:string |
| http://purl.uniprot.org/citations/18000606 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/18000606 |
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