We present the first structure of a noncovalent inhibitor bound to the protease domain of hepatitis C virus NS3 protein (NS3p), solved by NMR. The inhibitor exploits interactions with the S' region of NS3p to form a long-lived complex, although the absence of negative charges strongly reduces the association rate. The inhibitor stabilizes the N-terminal domain of NS3p and the substrate-binding site, and correctly aligns catalytic His-Asp residues. These actions were previously attributed exclusively to the cofactor NS4A, which interacts with the N-terminal domain of the NS3p and functions as an activator in vivo. The structure of the inhibitor/NS3p complex is very similar to that of the NS3p-NS4A complex, showing that binding of the NS4A cofactor is not the only event leading to a stable activesite conformation. (C) 2008 Elsevier Ltd. All rights reserved.

Gallo, M., Pennestri, M., Bottomley, M., Barbato, G., Eliseo, T., Paci, M., et al. (2009). Binding of a Noncovalent Inhibitor Exploiting the S ' region Stabilizes the Hepatitis C virus NS3 Protease Conformation in the Absence of Cofactor. JOURNAL OF MOLECULAR BIOLOGY, 385(4), 1142-1155 [10.1016/j.jmb.2008.11.017].

Binding of a Noncovalent Inhibitor Exploiting the S ' region Stabilizes the Hepatitis C virus NS3 Protease Conformation in the Absence of Cofactor

PACI, MAURIZIO;CICERO, DANIEL OSCAR
2009-01-01

Abstract

We present the first structure of a noncovalent inhibitor bound to the protease domain of hepatitis C virus NS3 protein (NS3p), solved by NMR. The inhibitor exploits interactions with the S' region of NS3p to form a long-lived complex, although the absence of negative charges strongly reduces the association rate. The inhibitor stabilizes the N-terminal domain of NS3p and the substrate-binding site, and correctly aligns catalytic His-Asp residues. These actions were previously attributed exclusively to the cofactor NS4A, which interacts with the N-terminal domain of the NS3p and functions as an activator in vivo. The structure of the inhibitor/NS3p complex is very similar to that of the NS3p-NS4A complex, showing that binding of the NS4A cofactor is not the only event leading to a stable activesite conformation. (C) 2008 Elsevier Ltd. All rights reserved.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/10
English
Con Impact Factor ISI
cofactor; Hepatitis C virus; inhibitors; NMR; NS3 protease
Gallo, M., Pennestri, M., Bottomley, M., Barbato, G., Eliseo, T., Paci, M., et al. (2009). Binding of a Noncovalent Inhibitor Exploiting the S ' region Stabilizes the Hepatitis C virus NS3 Protease Conformation in the Absence of Cofactor. JOURNAL OF MOLECULAR BIOLOGY, 385(4), 1142-1155 [10.1016/j.jmb.2008.11.017].
Gallo, M; Pennestri, M; Bottomley, M; Barbato, G; Eliseo, T; Paci, M; Narjes, F; De Francesco, R; Summa, V; Koch, U; Bazzo, R; Cicero, Do
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/25714
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