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Published on: December 21, 2019
Structural basis for specificity in the poxvirus topoisomerase
Kay Perry1, Young Hwang, Frederic D Bushman
1University of Pennsylvania School of Medicine, Department of Biochemistry and Biophysics and Howard Hughes Medical Institute, Philadelphia, Pennsylvania 19104, USA.
Molecular Cell
|August 4, 2006
Summary
Researchers revealed crystal structures of the smallpox virus topoisomerase enzyme bound to DNA. These structures illuminate the enzyme's unique DNA recognition and activation mechanisms, aiding in antiviral drug design.
Area of Science:
- Structural Biology
- Virology
- Biochemistry
Background:
- Smallpox, though eradicated, poses a bioterrorism threat.
- The smallpox virus possesses a unique topoisomerase enzyme essential for its replication.
- This enzyme requires a specific DNA sequence for catalytic activation, differing from human topoisomerases.
Purpose of the Study:
- To elucidate the structural basis of site-specific DNA recognition by the smallpox virus topoisomerase.
- To understand the mechanism of catalysis activation through enzyme-DNA interactions.
- To provide a structural framework for developing therapeutics against poxvirus infections.
Main Methods:
- X-ray crystallography was employed to determine the structures.
- The study involved analyzing smallpox virus topoisomerase enzyme complexed with specific DNA sequences.
- Both covalently and non-covalently bound complexes were characterized.
Main Results:
- Crystal structures revealed how the smallpox virus topoisomerase recognizes specific DNA sequences.
- The study identified a unique major groove binding alpha helix in the poxvirus enzyme, absent in human counterparts.
- This helix was shown to be crucial for both DNA recognition and catalysis activation.
Conclusions:
- The determined structures provide detailed insights into the unique enzymatic mechanism of the smallpox virus topoisomerase.
- The findings highlight a key difference between viral and human topoisomerases, specifically in DNA binding and activation.
- These structural insights can guide the rational design of novel antiviral agents targeting poxvirus infections.
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