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First 3-D image of AIDS virus protein.

First 3-D image of AIDS virus protein

Researchers this week reported determining the three-dimensional structure of a key protein in the AIDS-causing virus, HIV. The protein -- a virally produced enzyme called aspartyl protease that is critical to HIV replication -- is the first HIV protein to have its 3-D structure revealed. An understanding of the enzyme's structure, and by extension, its function, opens a new approach for the design of drugs that would specifically block HIV replication.

Manuel A. Navia of Merck Sharp and Dohme Research Laboratories in Rahway, N.J., and his co-workers used X-ray crystallography techniques to create the image of aspartyl protease -- one of only three enzymes produced by the simple but deadly HIV. (AZT, the only anti-HIV drug to gain U.S. approval, targets another HIV enzyme, reverse transcriptase.) The protease cleaves large, freshly produced viral proteins into smaller, functional subunits. Inside an infected mammalian cell, those subunits assemble into new AIDS viruses.

Scientists have found similar proteases in other organisms, but to design a drug specifically against HIV they needed a detailed picture of the HIV version. They especially wanted an image of the enzyme's active site -- the three-dimensional cleft into which proteins in need of cleaving nestle. With a clear picture of that site's molecular topography, researchers will seek to design molecules that mimic the enzyme's protein target, or substrate, but that block the enzyme's activity.

The newly reported image, in the Feb. 16 NATURE, is of only "medium" resolution, notes Alexander Wlodawer of the National Cancer Institute-Frederick (Md.) Cancer Research Facility. But "there is very little doubt that the substrate-binding pocket is described reasonably well."

Higher-resolution images should provide important details about hydrogen bonding between enzyme and substrate, he says. And future images of the enzyme bound to experimental inhibitors may suggest new approaches to blocking the enzyme's activity. Even then, he cautions, there remains the problem of drug delivery. "It's not only the protein that you have to look at, but you have to get it into the cell."

Wlodawer and his colleagues provided the first three-dimensional picture of a closely related protease earlier this month. Working from that image, he and others provide a predicted structure of HIV aspartyl protease in the Feb. 17 SCIENCE very similar to the Merck team's image.
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Title Annotation:aspartyl protease
Author:Weiss, Rick
Publication:Science News
Date:Feb 18, 1989
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