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 active-site conformation.

Binding of a Noncovalent Inhibitor Exploiting the S′ region Stabilizes the Hepatitis C virus NS3 Protease Conformation in the Absence of Cofactor / M. Gallo, M. Pennestri, M.J. Bottomley, G. Barbato, T. Eliseo, M. Paci, F. Narjes, R. De Francesco, V. Summa, U. Koch, R. Bazzo, D.O. Cicero. - In: JOURNAL OF MOLECULAR BIOLOGY. - ISSN 0022-2836. - 385:4(2009), pp. 1142-1155.

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

R. De Francesco;
2009

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 active-site conformation.
Hepatitis C virus; NS3 protease; inhibitors; cofactor; NMR
Settore BIO/19 - Microbiologia Generale
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/634751
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