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Inhibitor binding induces active site stabilization of the HCV NS3 protein serine protease domain
Author(s) -
Barbato G,
Cicero D.O.,
Cordier F,
Narjes F,
Gerlach B,
Sambucini S,
Grzesiek S,
Matassa V.G.,
De Francesco R.,
Bazzo R
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.6.1195
Subject(s) - biology , serine protease , ns3 , masp1 , serine , active site , protease , protease inhibitor (pharmacology) , binding site , plasma protein binding , virology , biochemistry , enzyme , virus , antiretroviral therapy , viral load
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.