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August 27, 2004|Volume 33, Number 1



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Researchers discover how Hepatitis C
enzyme unwinds RNA

Research led by Anna Marie Pyle, professor of molecular biophysics and biochemistry, reveals how a protein from Hepatitis C (HCV) unwinds RNA, potentially allowing it be copied.

The work, published in the journal Nature, focuses on an enzyme -- helicase NS3 -- that unwinds the RNA virus for replication inside cells. NS3 is one member of an extensive family of helicases and is used as a model for studying unwinding activities of motor proteins.

The team's findings are considered particularly important because NS3 is a major drug target against HCV and understanding the helicase function will aid in the development of HCV inhibitors.

Pyle's results contradict the idea that helicases move smoothly with the continuous action of a snow plow. Instead, NS3 moves with a discontinuous stepping motion that alternates rapid translocation with pausing. "We observe that the helicase proceeds through discreet spatial and kinetic microstates," Pyle says. "We actually track the speed and processivity of the helicase as it passes through each base pair of its substrate."

"While this report is the first of its kind, and has produced highly significant results, it is only the beginning of a new understanding in HCV enzymology," says Pyle. "In the future, our approaches will be used to understand the composition of the HCV replication complex and the interplay between its constituent proteins. Comparative studies will be done on other viruses and in other systems where helicase function is critical."

These novel features were revealed using a new type of combinatorial enzymology that allows the behavior of helicase enzymes to be directly compared on a sequence panel. This is the first time that the behavior of a nucleic acid remodeling protein has been monitored at this high resolution, as it acts upon or passes each subunit of its target, according to Pyle. Since the work was conducted on RNA, it helps to bring RNA helicases to the forefront of motor research.

"By visualizing one of the key steps in how hepatitis C makes copies of itself, Dr. Pyle unexpectedly discovered that the molecular motor that unzips the virus' genetic material looks a lot like the motor that drives muscles," says Dr. Richard Ikeda, a chemist at the National Institute of General Medical Sciences, which funded the work. "This is a perfect example of how a basic investigation revealed surprise insights into the similarities among widely different organisms."

The work was co-authored by postdoctoral fellow Victor Serebrov and was also funded by grants from the National Institutes of Health and the Howard Hughes Medical Institute.

-- By Janet Rettig Emanuel


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New M.B.A. program to train healthcare industry leaders

YALE LIBRARY NEWS

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Air travel generally safe for cardiovascular patients, say scientists

Team's findings open new path for treatment of lung disease

Investigators get first look at atomic structure . . .

Scientists unravel how animals sense and distinguish odors

Studies show effects of transplanted bone marrow cells

Researchers discover how Hepatitis C enzyme unwinds RNA

Study reveals patterns of behavior associated with maintaining weight loss

Research underscores value of beta-blockers in treating heart patients

Report: Many older patients choose treatments . . .

Investigators' work offers insights into the biology of depression

Researchers win grants for research on women's health

Child Study Center receives grant to assess IICAPS

Yale physicians named 'top doctors' by colleagues in magazine poll

Maihle to chair Women in Cancer Research Council

'Chasing Rainbows' now on view in Yale Rep plaz

Campus Notes


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