Thumb inhibitor binding eliminates functionally important dynamics in the hepatitis C virus RNA polymerase

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dc.contributor.authorDavis, Brittny C.
dc.contributor.authorThorpe, Ian F.
dc.date.accessioned2018-10-01T14:06:21Z
dc.date.available2018-10-01T14:06:21Z
dc.date.issued2012-07-31
dc.description.abstractHepatitis C virus (HCV) has infected almost 200 million people worldwide, typically causing chronic liver damage and severe complications such as liver failure. Currently, there are few approved treatments for viral infection. Thus, the HCV RNA‐dependent RNA polymerase (gene product NS5B) has emerged as an important target for small molecule therapeutics. Potential therapeutic agents include allosteric inhibitors that bind distal to the enzyme active site. While their mechanism of action is not conclusively known, it has been suggested that certain inhibitors prevent a conformational change in NS5B that is crucial for RNA replication. To gain insight into the molecular origin of long‐range allosteric inhibition of NS5B, we employed molecular dynamics simulations of the enzyme with and without an inhibitor bound to the thumb domain. These studies indicate that the presence of an inhibitor in the thumb domain alters both the structure and internal motions of NS5B. Principal components analysis identified motions that are severely attenuated by inhibitor binding. These motions may have functional relevance by facilitating interactions between NS5B and RNA template or nascent RNA duplex, with presence of the ligand leading to enzyme conformations with narrower and thus less accessible RNA binding channels. This study provides the first evidence for a mechanistic basis of allosteric inhibition in NS5B. Moreover, we present evidence that allosteric inhibition of NS5B results from intrinsic features of the enzyme free energy landscape, suggesting a common mechanism for the action of diverse allosteric ligands. Proteins 2013. © 2012 Wiley Periodicals, Inc.en_US
dc.description.sponsorshipGrant sponsor: US National Science Foundation; Grant number: CNS-0821258; Grant sponsor: SCREMS Program; Grant number: DMS-0821311; Grant sponsor: National Science Foundation; Grant number: OCI-1053575; Grant sponsor: University of Maryland, Baltimore County (UMBC) Much of the hardware used in this study is part of the UMBC High Performance Computing Facility (HPCF). In addition, this work used the Extreme Science and Engineering Discovery Environment (XSEDE).en_US
dc.description.urihttps://onlinelibrary.wiley.com/doi/full/10.1002/prot.24154en_US
dc.format.extent24 pagesen_US
dc.genrejournal articleen_US
dc.identifierdoi:10.13016/M29G5GH8J
dc.identifier.citationBrittny C. Davis, Ian F. Thorpe, Thumb inhibitor binding eliminates functionally important dynamics in the hepatitis C virus RNA polymerase, Proteins. 2013 January ; 81(1): 40–52. doi:10.1002/prot.24154.en_US
dc.identifier.urihttps://doi.org/10.1002/prot.24154
dc.identifier.urihttp://hdl.handle.net/11603/11424
dc.language.isoen_USen_US
dc.publisherWileyen_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Chemistry & Biochemistry Department Collection
dc.relation.ispartofUMBC Faculty Collection
dc.rightsThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
dc.subjectallosteryen_US
dc.subjectnon-nucleoside inhibitoren_US
dc.subjectconformational changeen_US
dc.subjectNS5B polymeraseen_US
dc.subjectmolecular simulationen_US
dc.subjectUMBC High Performance Computing Facility (HPCF)en_US
dc.titleThumb inhibitor binding eliminates functionally important dynamics in the hepatitis C virus RNA polymeraseen_US
dc.typeTexten_US

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