Structural basis for specificity in the poxvirus topoisomerase.

Abstract

Although smallpox has been eradicated from the human population, it is presently feared as a possible agent of bioterrorism. The smallpox virus codes for its own topoisomerase enzyme that differs from its cellular counterpart by requiring a specific DNA sequence for activation of catalysis. Here we present crystal structures of the smallpox virus topoisomerase enzyme bound both covalently and noncovalently to a specific DNA sequence. These structures reveal the basis for site-specific DNA recognition, and they explain how catalysis is likely activated by formation of a specific enzyme-DNA interface. Unexpectedly, the poxvirus enzyme uses a major groove binding alpha helix that is not present in the human enzyme to recognize part of the core recognition sequence and activate the enzyme for catalysis. The topoisomerase-DNA complex structures also provide a three-dimensional framework that may facilitate the rational design of therapeutic agents to treat poxvirus infections.

• Authors: Kay Perry, Young Hwang, Frederic D Bushman, Gregory D Van Duyne
• Journal: Molecular cell (Mol Cell) Vol. 23 Issue 3 Pg. 343-54 (Aug 04 2006) ISSN: 1097-2765 [Print] United States
• PMID: 16885024 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antiviral Agents
• DNA, Superhelical
• Enzyme Inhibitors
• Recombinant Proteins
• Topoisomerase I Inhibitors
• DNA Topoisomerases, Type I
• Camptothecin

Topics

• Antiviral Agents (chemistry, pharmacology)
• Camptothecin (chemistry, pharmacology)
• Catalysis
• Catalytic Domain (genetics)
• Crystallography, X-Ray
• DNA Topoisomerases, Type I (chemistry, genetics)
• DNA, Superhelical (chemistry, genetics, metabolism)
• Enzyme Inhibitors (chemistry, pharmacology)
• Models, Molecular
• Mutation (genetics)
• Mutation, Missense (genetics)
• Nucleic Acid Conformation
• Protein Binding
• Protein Conformation
• Protein Structure, Secondary
• Recombinant Proteins (antagonists & inhibitors, chemistry, metabolism)
• Structure-Activity Relationship
• Topoisomerase I Inhibitors
• Variola virus (enzymology, genetics)