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Scientists visualize how a vital hepatitis C virus protein moves along its nucleic acid substrate

Date:
January 4, 2010
Source:
Rockefeller University
Summary:
By taking three conformational snapshots of a hepatitis C virus motor protein in association with its substrate, researchers have provided the first structural explanation of how a representative superfamily 2 helicase moves unidirectionally along nucleic acid, suggesting new ways that drug designers could block virus replication.
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Motoring. By piecing together three molecular snapshots, scientists reveal how a vital hepatitis C protein moves along its nucleic acid substrate. Developing drugs that specifically disrupt the movement of this protein, known as NS3, would prevent the hepatitis C virus from replicating without affecting its host.
Credit: Image courtesy of Rockefeller University

By taking three conformational snapshots of a hepatitis C virus motor protein in association with its substrate, researchers at Rockefeller University have provided the first structural explanation of how a representative superfamily 2 helicase moves unidirectionally along nucleic acid, suggesting new ways that drug designers could block virus replication.

It has long been known that triphosphate nucleotides, such as ATP, are required to power the movement of the HCV NS3 helicase, and crystal structures of NS3 were solved long ago. Now reporting in the Proceedings of the National Academy of Sciences, Charles M. Rice, head of the Laboratory of Virology and Infectious Disease, and Meigang Gu, a postdoc in the lab,

show how ATP successively remodels the contacts between the substrate and NS3 and pinpoint key elements that play a role in the helicase translocation.

"There are key transitions that occur to NS3 and DNA when ATP binds the protein and when ATP proceeds into the transition state of hydrolysis," says Gu. "Targeting the elements involved in these transitions could inhibit the helicase and stop the virus from replicating."

In a series of three molecular snapshots, Rice and Gu capture details of how NS3 moves along its nucleic acid substrate. They show that when bound to DNA, the protein resembles the Greek letter lambda. When the protein-DNA complex binds ATP, lambda's back leg sweeps forward to meet its front, closing the space between them -- a move that is associated with the back leg's weak grip on DNA. Then, as ATP hydrolysis proceeds, lambda's back leg springs toward DNA and regrips it. It's like a stealthy cartoon character tiptoeing with exaggerated steps.

A key component of this process is unidirectional movement of a phosphate group in the middle of the DNA strand. As the back leg sweeps forward, the front leg detaches itself from this phosphate, allowing it to form water-mediated interactions with the back leg, which stretches to recapture this phosphate group in the transition state. By reconstituting the actions of the helicase, Rice and Gu found that one ATP molecule propels NS3 forward by one genetic letter.

"Like the actions of a ratchet, the successive transitions within NS3 prevent phosphate 3 from walking in the opposite direction," explains Gu. "This mechanism is likely adopted by other superfamily 2 DExH helicases with similar motifs, especially a newly defined motif Y."

The atomic details of ATP and DNA binding in different conformational states provide additional insights into drug development. "The advantage of targeting these sites is that the virus should have difficulty generating resistance through simple point mutations," says Rice.


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The above post is reprinted from materials provided by Rockefeller University. Note: Materials may be edited for content and length.


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Rockefeller University. "Scientists visualize how a vital hepatitis C virus protein moves along its nucleic acid substrate." ScienceDaily. ScienceDaily, 4 January 2010. <www.sciencedaily.com/releases/2009/12/091231150452.htm>.
Rockefeller University. (2010, January 4). Scientists visualize how a vital hepatitis C virus protein moves along its nucleic acid substrate. ScienceDaily. Retrieved August 4, 2015 from www.sciencedaily.com/releases/2009/12/091231150452.htm
Rockefeller University. "Scientists visualize how a vital hepatitis C virus protein moves along its nucleic acid substrate." ScienceDaily. www.sciencedaily.com/releases/2009/12/091231150452.htm (accessed August 4, 2015).

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