Study uncovers multitasking skill of HIV enzyme

May 8th, 2008 - 7:36 pm ICT by admin  

London, May 8 (ANI): Scientists have discerned how a single key enzyme differentiates and dynamically binds both DNA and RNA as part of HIVs fierce attack on host cells.

The new finding results from a study led by Xiaowei Zhuang of Harward University and Stuart Le Grice of the National Cancer Institute.

The researchers have revealed that the enzyme they studied, reverse transcriptase (RT), is already the target of two of the three major classes of existing anti-HIV drugs.

In the new study, the research team used a single-molecule fluorescent imaging to trace the enzymes activity in real time.

They say that their study work not only provides insights into how this critical viral enzyme functions, but also unravels how some of the anti-HIV medicines work.

“Our experiments allowed us, for the first time, a peek at how individual RT molecules interact with the HIV genome. We found that RT binds RNA and DNA primers with opposite orientations and that RT’s function is dictated by this binding orientation,” Nature magazine quoted Zhuang as saying.

In their study report, the researchers have revealed that HIV begins its assault by injecting its single-stranded RNA into a host cell, and then three subsequent steps are all mediated by RTthe conversion of the viral RNA into single-stranded DNA, replication of the single-stranded DNA into double-stranded DNA, and degradation of the original viral.

The report further states that another enzyme mediates the final step of the genome conversion, where the viral double-stranded DNA is inserted into the host’s DNA, allowing it to take advantage of the host’s genetic machinery to replicate and propagate itself.

A molecular probe was launched to spy on this process during the study, which helped the researchers trace RT’s multitasking skill to its dynamic active sites that allow it to bind and process RNA as well as single or double-stranded DNA.

“Remarkably, RT can spontaneously flip between these two opposite orientations on DNA and RNA to facilitate two distinct catalytic activities,” said Elio A. Abbondanzieri, a postdoctoral researcher in Harvard’s Department of Chemistry and Chemical Biology who jointly authored the study with Gregory Bokinsky of the Lawrence Berkeley National Laboratory.

“These flipping motions, which have never before been seen in a protein-nucleic acid complex, can be likened to a nanoscale version of a gymnastics routine on a pommel horse,” Abbondanzieri added.

The studys authors have found that the 180-degree flipping of RT is regulated by non-nucleoside RT inhibitors (NNRTIs), a major class of anti-HIV drugs.

They have observed NNRTIs inhibiting HIV activity by accelerating RT’s flipping between its two active sites, hindering the enzyme’s ability to convert single-stranded DNA to double-stranded DNA. (ANI)

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