environmental factor - november 2012_ study offers insight into hiv metal and ligand binding
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7/15/14 2:06 PMEnvironmental Factor - November 2012: Study offers insight into HIV metal and ligand binding
Page 1 of 3http://www.niehs.nih.gov/news/newsletter/2012/11/science-hiv/index.htm
Environmental Factor, November 2012
London’s NMR Group studiesthe molecular mechanisms thatunderlie problems ofenvironmental concern. (Photocourtesy of Steve McCaw)
Research Fellow Xunhai Zheng,
Study offers insight into HIV metal and ligand bindingBy Cindy Loose
A discovery by scientists in the NIEHS Laboratory of StructuralBiology (LSB) opens the door for developing new treatments forhuman immunodeficiency virus (HIV). Members of the LSB NuclearMagnetic Resonance (NMR) Group, headed by Robert London,Ph.D., identified a new, highly sensitive probe that can monitor thebinding of compounds to a viral enzyme that allows HIV to infecthumans. The finding is particularly critical, as some patients becomeresistant to existing antivirals for HIV.
“The HIV virus is a moving target, due to its exceptionally high abilityto mutate,” London said. “This allows it to escape existing drugtherapies. Hence, additional strategies are needed to interfere withthe virus.”
London and three members of his group published their findings(http://www.ncbi.nlm.nih.gov/pubmed/22941642) online Aug. 31 inthe publication Nucleic Acids Research.
The critical role of the RNase H domain
Understanding the breakthrough requires information about how thevirus and current treatments work. HIV is a retrovirus, meaning itstores its genome as RNA instead of DNA, explained staff scientistand paper co-author Geoffrey Mueller, Ph.D. The virus has toconvert the single-stranded RNA into double-stranded DNA to infectthe host cell. It does so in a three-step process. First, it copies theRNA into DNA creating an RNA:DNA hybrid molecule. Second, itdestroys the RNA part of the RNA:DNA hybrid. Third, it copies theremaining single strand of DNA to make double-stranded DNA thateventually infects the host.
According to Mueller, most treatments currently available targetsteps one and three. They do so by interrupting, or inhibiting, theprocess by which the viral genome is copied. So far, none of thedrugs inhibit step two, which is the destruction of the old RNAgenome. Mueller believes the new discovery could allow scientists totarget this activity, which is carried out by the RNase H domain of thereverse transcriptase enzyme. The RNase H domain is consideredequally essential to the replication of the HIV virus as the polymerasedomain that is currently targeted by existing treatments.
7/15/14 2:06 PMEnvironmental Factor - November 2012: Study offers insight into HIV metal and ligand binding
Page 2 of 3http://www.niehs.nih.gov/news/newsletter/2012/11/science-hiv/index.htm
Research Fellow Xunhai Zheng,Ph.D., is first author on thepaper. (Photo courtesy of SteveMcCaw)
Eugene DeRose, Ph.D., is a co-author and serves as NMR Mueller was instrumental is
NMR
The new probe identified by London and colleagues can monitor thebinding of compounds to the RNase H domain. They found that oneof the residues of the protein had a characteristic signature whencompounds bound, despite the residue being very distant from the active site. Using NuclearMagnetic Resonance (NMR) spectroscopy, they realized that the residue is a good probe of what’sin the active site. Their results will allow scientists who are testing a treatment intended to inhibitthe HIV virus to see whether or not the potential drug is binding to the RNase H domain and havingan effect.
NMR is a research technique that exploits the magnetic properties of atomic nuclei to studymolecules. It can provide detailed information about the structure, dynamics, chemicalenvironment, and even the reactions of molecules.
“There had been attempts to identify inhibitors of RNase H activity, but because it has such astrange active site, the work has been difficult,” said Mueller. “This finding advances the goal offinding an antiviral that works on this domain.”
The group plans to continue work on understanding the RNase H domain and its promise as adrug target.
Citation: Zheng X, Mueller GA, DeRose EF, London RE.(http://www.ncbi.nlm.nih.gov/pubmed/22941642) 2012. Metal and ligand binding to the HIV-RNaseH active site are remotely monitored by Ile556. Nucleic Acids Res; doi:10.1093/nar/gks791 [Online31 August 2012].
(Cindy Loose is a contract writer with the NIEHS office in Bethesda, Md.)
7/15/14 2:06 PMEnvironmental Factor - November 2012: Study offers insight into HIV metal and ligand binding
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Center Manager. (Photocourtesy of Steve McCaw)
Mueller was instrumental isexplaining the science for thisEnvironmental Factor article.(Photo courtesy of SteveMcCaw)
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