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Insights into RNA unwinding and ATP hydrolysis by the flavivirus NS3 protein.

Luo, Dahai and Xu, Ting and Watson, Randall and Scherer-Becker, Daniela and Sampath, Aruna and Jahnke, Wolfgang and Yeong, Sui Sum and Wang, Chern Hoe and Lim, Siew Pheng and Strongin, Alex and Vasudevan, Subhash and Lescar, Julien (2008) Insights into RNA unwinding and ATP hydrolysis by the flavivirus NS3 protein. The EMBO Journal, 27 (23). pp. 3209-3219. ISSN 1460-2075

Abstract

Together with the NS5 polymerase, the NS3 helicase has a pivotal function in flavivirus RNA replication and constitutes an important drug target. We captured the dengue virus NS3 helicase at several stages along the catalytic pathway including bound to single-stranded (ss) RNA, to an ATP analogue, to a transition-state analogue and to ATP hydrolysis products. RNA recognition appears largely sequence independent in a way remarkably similar to eukaryotic DEAD box proteins Vasa and eIF4AIII. On ssRNA binding, the NS3 enzyme switches to a catalytic-competent state imparted by an inward movement of the P-loop, interdomain closure and a change in the divalent metal coordination shell, providing a structural basis for RNA-stimulated ATP hydrolysis. These structures demonstrate for the first time large quaternary changes in the flaviviridae helicase, identify the catalytic water molecule and point to a beta-hairpin that protrudes from subdomain 2, as a critical element for dsRNA unwinding. They also suggest how NS3 could exert an effect as an RNA-anchoring device and thus participate both in flavivirus RNA replication and assembly.

Item Type: Article
Related URLs:
Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: ATP analogues; dengue virus; flaviviruses; NS3 helicase structure; RNA complex
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Date Deposited: 14 Dec 2009 13:48
Last Modified: 31 Jan 2013 00:56
URI: https://oak.novartis.com/id/eprint/1340

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