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Book of Abstracts: Albany 2003

category image Albany 2003
Conversation 13
Abstract Book
June 17-21 2003

A Role for Z-DNA Binding in Vaccinia Virus Pathogenesis

Negative supercoiling of DNA generated during transcription stabilizes its left-handed Z-DNA conformation. Proteins that bind selectively to Z-DNA also stabilize that conformation. Two human protein domains have been isolated that bind to Z-DNA with conformational specificity, as shown by crystal structures of the protein - Z-DNA complexes. The two proteins differ considerably in sequence but their Z-DNA interactions are similar. A third member of this class is the E3L protein of pox viruses. The lethality of vaccinia virus for a mouse depends upon the presence of the E3L viral gene product. When the E3L domain of vaccinia virus is removed and replaced with either of the two Z-DNA binding proteins whose crystal structure is known, the virus retains lethality. However, when mutations are made in the Z-DNA binding proteins that weaken binding to Z-DNA, a lessening of virulence is seen. When a protein that does not bind Z-DNA is incorporated into the E3L position, the virus is not lethal. However, if that protein is mutated so that it does bind Z-DNA, the virus becomes lethal. Z-DNA binding by the E3L protein is thus an essential component of virulence in vaccinia viruses. It is likely that a small molecule can be found that would attach to the Z-DNA binding site of the protein and thereby prevent virulence of vaccinia virus in mice. Since variola, the agent of smallpox has a virtually identical E3L molecule, it is likely that this small molecule will also prevent the pathology of smallpox.

Yang-Gyun Kim4
Maneesha Muralinath2
Teresa Brandt2
Matthew Pearcy2
Kevin Hauns2
Ky Lowenhaupt1
Bertram L. Jacobs2,3
Alexander Rich1

1Dept.of Biology
MIT
Rm. 68-233
77 Massachusetts Avenue
Cambridge, MA 02139-4307 USA
2Graduate Program in Molecular &Cellular Biology
Arizona State University
Tempe, AZ 85287-2701USA
3Dept.of Microbiology
Arizona State University
Tempe, AZ 85287-2701USA
4Dept.of Biochemistry
College of Medicine
Chung-Ang University
221 Heuksuk-dong
Dongjak-gu, Seoul 156-756, Korea
cbeckman@mit.edu