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Inhibitor binding induces active site stabilization of the HCV NS3 protein serine protease domain

Barbato, G. and Cicero, D. O. and Cordier, F. and Narjes, F. and Gerlach, B. and Sambucini, S. and Grzesiek, S. and Matassa, V. G. and De Francesco, R. and Bazzo, R.. (2000) Inhibitor binding induces active site stabilization of the HCV NS3 protein serine protease domain. The EMBO journal, Vol. 19, H. 6. pp. 1195-1206.

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Official URL: http://edoc.unibas.ch/dok/A5258803

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Abstract

Few structures of viral serine proteases, those encoded by the Sindbis and Semliki Forest viruses, hepatitis C virus (HCV) and cytomegalovirus, have been reported. In the life cycle of HCV a crucial role is played by a chymotrypsin-like serine protease encoded at the N- terminus of the viral NS3 protein, the solution structure of which we present here complexed with a covalently bound reversible inhibitor. Unexpectedly, the residue in the P2 position of the inhibitor induces an effective stabilization of the catalytic His-Asp hydrogen bond, by shielding that region of the protease from the solvent. This interaction appears crucial in the activation of the enzyme catalytic machinery and represents an unprecedented observation for this family of enzymes. Our data suggest that natural substrates of this serine protease could contribute to the enzyme activation by a similar induced- fit mechanism. The high degree of similarity at the His-Asp catalytic site region between HCV NS3 and other viral serine proteases suggests that this behaviour could be a more general feature for this category of viral enzymes.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
UniBasel Contributors:Grzesiek, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Nature Publishing Group
ISSN:0261-4189
Note:Publication type according to Uni Basel Research Database: Journal article
Last Modified:22 Mar 2012 14:20
Deposited On:22 Mar 2012 13:21

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