NIGMS Office of Communications and Public Liaison
AZT and many other anti-AIDS drugs target an enzyme in the human immunodeficiency virus (HIV) known as reverse transcriptase. This enzyme translates the virus' genetic material into a form that can insert itself into human chromosomes. The virus then commandeers the infected cell, forcing it to produce new virus particles.
AZT works by stopping reverse transcriptase's translation mid-word. But some, slightly altered versions of the enzyme--which are present in almost every person with HIV--can evade AZT's effects. Virus particles containing these forms of the enzyme multiply, and eventually, AZT is no longer effective against the virus. Everyone receiving AZT alone develops such resistance to it--and can spread the resistant virus to others.
Scientists have been trying for years to determine the structure of reverse transcriptase in its active form. These researchers succeeded by using an innovative chemical technique to tether the enzyme to its natural biochemical partners.
The detailed, three-dimensional snapshot reveals in atomic detail how the enzyme foils AZT, and reveals a possible target for new anti-AIDS therapies.
Reverse transcriptase is shaped something like a relaxed hand. The new structure reveals that, as the enzyme translates viral genetic material from RNA into DNA, the "hand" clenches around the growing DNA strand. AZT stops the process by capping the growing end of the DNA strand. The structure confirmed what many scientists had suspected for years--that most of the mutations that make the enzyme resistant to AZT cluster around the capping site, where the drug binds to DNA.
The new information reveals, at a molecular level, how HIV becomes resistant to AZT-like drugs. It also provides detailed insight into how to develop better anti-AIDS drugs. For example, the researchers found a small pocket that, if plugged by a drug, might shut down reverse transcriptase, and thus halt viral replication. This pocket is a possible target for future anti-AIDS drugs.
The work will also improve current understanding of how similar proteins in other viruses work, and how these proteins might contribute to other types of drug-resistant viruses. The new knowledge is of major importance: more than 33 million people worldwide are infected with HIV/AIDS. Almost 14 million people have died from the disease.
Huang H, Chopra R, Verdine GL, Harrison SC. Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance.
Science 1998;282: 1669-75.
Balter M. Outsmarting HIV Drug Resistance.
Science 1998;282:1623-5. (News section)
Borman S. Catalytic complex of HIV enzyme analyzed.
Chemical and Engineering News, November 30, 1998; p. 7-8. (News section)
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NIGMS Office of Communications and Public Liaison at (301) 496-7301 to obtain the name of a scientist in the NIGMS Division of Cell Biology and Biophysics who can comment on this work.
This page last reviewed on
12/4/2018 3:03 PM
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