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Publication Abstract from PubMed

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.,Gallo M, Pennestri M, Bottomley MJ, Barbato G, Eliseo T, Paci M, Narjes F, De Francesco R, Summa V, Koch U, Bazzo R, Cicero DO J Mol Biol. 2009 Jan 30;385(4):1142-55. Epub 2008 Nov 24. PMID:19061898^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.