TAILIEUCHUNG - Báo cáo khoa học: Crystal structure of a staphylokinase variant A model for reduced antigenicity

Staphylokinase (SAK) is a protein fromStaphy-lococcus aureusthat activates plasminogenby forminga1 : 1 complex with plasmin. Recombinant SAK has been shown in clinical trials to induce ®brin-speci®c clot lysis in patients withacutemyocardial , SAKelicits high titers of neutralizing antibodies. Biochemical and protein engineering studies have demonstrated the feasibility of generatingSAKvariantswith reducedantigenicity yet intact thrombolytic potency. | Eur. J. Biochem. 269 705-711 2002 FEBS 2002 Crystal structure of a staphylokinase variant A model for reduced antigenicity Yuhana Chen1. Gana Sona2. Fan Jiang1. Liana Fena1. Xiaoxuan Zhana1. Yi Dina1. Mark Bartlam1 B B B B B B Ao Yana1 Xiana Ma1 Shena Ye1 Yiwei Liu1 Hona Tana1 Houyan Sona2 and Zihe Rao1 1 Laboratory of Structural Biology MOE Laboratory of Protein Science Tsinghua University Beijing China department of Molecular Genetics Shanghai Medical University China Staphylokinase SAK is a protein from Staphylococcus aureus that activates plasminogen by forming a 1 1 complex with plasmin. Recombinant SAK has been shown in clinical trials to induce fibrin-specific clot lysis in patients with acute myocardial infarction. However SAK elicits high titers of neutralizing antibodies. Biochemical and protein engineering studies have demonstrated the feasibility of generating SAK variants with reduced antigenicity yet intact thrombolytic potency. Here we present X-ray crystallographic evidence that the SAK S41G mutant may assume a dimeric structure. This dimer model at resolution could explain a major antigenic epitope residues A72-F76 and residues K135-K136 located in the vicinity of the dimer interface as identified by phage-display. These results suggest that SAK antigenicity may be reduced by eliminating dimer formation. We propose several potential mutation sites at the dimer interface that may further reduce the antigenicity ofSAK. Keywords staphylokinase dimer crystal structure antigenicity protein engineering. Staphylokinase SAK is a 136-amino-acid protein produced by the lysogenic phase of Staphylococcus aureus and has been found to be a thrombolytic agent 1-3 with potency similar to streptokinase SK . Unlike the endogenous urokinase uPA and tissue-type plasminogen activator tPA SAK has no proteolytic activity. Similar to SK SAK acts as a cofactor to form a 1 1 complex with human plasmin ogen . The SAK-plasmin cofactor-enzyme complex which has .

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