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Environmental Factor, November 2012

Study offers insight into HIV metal and ligand binding

By Cindy Loose

Robert London, Ph.D.

London’s NMR Group studies the molecular mechanisms that underlie problems of environmental concern. (Photo courtesy of Steve McCaw)

Xunhai Zheng, Ph.D.

Research Fellow Xunhai Zheng, Ph.D., is first author on the paper. (Photo courtesy of Steve McCaw)

A discovery by scientists in the NIEHS Laboratory of Structural Biology (LSB) opens the door for developing new treatments for human immunodeficiency virus (HIV). Members of the LSB Nuclear Magnetic Resonance (NMR) Group, headed by Robert London, Ph.D., identified a new, highly sensitive probe that can monitor the binding of compounds to a viral enzyme that allows HIV to infect humans. The finding is particularly critical, as some patients become resistant to existing antivirals for HIV.

“The HIV virus is a moving target, due to its exceptionally high ability to mutate,” London said. “This allows it to escape existing drug therapies. Hence, additional strategies are needed to interfere with the virus.”

London and three members of his group published their findings (http://www.ncbi.nlm.nih.gov/pubmed/22941642)  online Aug. 31 in the publication Nucleic Acids Research.

The critical role of the RNase H domain

Understanding the breakthrough requires information about how the virus and current treatments work. HIV is a retrovirus, meaning it stores its genome as RNA instead of DNA, explained staff scientist and paper co-author Geoffrey Mueller, Ph.D. The virus has to convert the single-stranded RNA into double-stranded DNA to infect the host cell. It does so in a three-step process. First, it copies the RNA into DNA creating an RNA:DNA hybrid molecule. Second, it destroys the RNA part of the RNA:DNA hybrid. Third, it copies the remaining single strand of DNA to make double-stranded DNA that eventually infects the host.

According to Mueller, most treatments currently available target steps one and three. They do so by interrupting, or inhibiting, the process by which the viral genome is copied. So far, none of the drugs inhibit step two, which is the destruction of the old RNA genome. Mueller believes the new discovery could allow scientists to target this activity, which is carried out by the RNase H domain of the reverse transcriptase enzyme. The RNase H domain is considered equally essential to the replication of the HIV virus as the polymerase domain that is currently targeted by existing treatments.

NMR

The new probe identified by London and colleagues can monitor the binding of compounds to the RNase H domain. They found that one of the residues of the protein had a characteristic signature when compounds bound, despite the residue being very distant from the active site. Using Nuclear Magnetic Resonance (NMR) spectroscopy, they realized that the residue is a good probe of what’s in the active site. Their results will allow scientists who are testing a treatment intended to inhibit the HIV virus to see whether or not the potential drug is binding to the RNase H domain and having an effect.

NMR is a research technique that exploits the magnetic properties of atomic nuclei to study molecules. It can provide detailed information about the structure, dynamics, chemical environment, and even the reactions of molecules.

“There had been attempts to identify inhibitors of RNase H activity, but because it has such a strange active site, the work has been difficult,” said Mueller. “This finding advances the goal of finding an antiviral that works on this domain.”

The group plans to continue work on understanding the RNase H domain and its promise as a drug 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-RNase H active site are remotely monitored by Ile556. Nucleic Acids Res; doi:10.1093/nar/gks791 [Online 31 August 2012].

(Cindy Loose is a contract writer with the NIEHS office in Bethesda, Md.)


Eugene DeRose, Ph.D.

Eugene DeRose, Ph.D., is a co-author and serves as NMR Center Manager. (Photo courtesy of Steve McCaw)


Geoffrey Mueller, Ph.D.

Mueller was instrumental is explaining the science for this Environmental Factor article. (Photo courtesy of Steve McCaw)




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