Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Penn researchers determine structure of smallpox virus protein bound to DNA

Structure could aid in anti-viral drug design

Researchers at the University of Pennsylvania School of Medicine have determined the structure of an important smallpox virus enzyme and how it binds to DNA. The enzyme, called a topoisomerase, is an important drug target for coming up with new ways to fight smallpox. The researchers present their findings in the August 4 issue of Molecular Cell.

"This enzyme is one of the most closely studied DNA-modifying enzymes in biology," says Frederic D. Bushman, PhD, Professor of Microbiology, one of the senior authors. "The structure of the DNA complex has been long-awaited." DNA-modifying enzymes bind to specific sequences in the genetic code to aid in the many steps of DNA replication.

The smallpox virus is one of the most easily transmissible infectious diseases known to humans, resulting in up to 30 percent mortality. The efficiency with which it spreads, combined with the deadly nature of the disease, has raised fears that smallpox could be revived for use in bioterrorism. Knowing the exact three-dimensional structure of smallpox virus proteins could help researchers design antiviral agents, but few structures of whole viral proteins exist.

Poxviruses are large viruses that contain two strands of DNA and replicate themselves entirely in the cytoplasm of infected cells. Poxviruses do not take over the genetic machinery inside the nucleus of the host cell, as many viruses do. Because of this strategy, poxviruses encode many of the enzymes they need to replicate their own genes, and hence reproduce. One of these enzymes is a topoisomerase, which is used by the virus to relieve the excessive twisting of DNA strands that normally occurs during DNA replication and transcription of the viral genes. Upon initial infection, the poxviruses come already equipped with some proteins, including topoisomerases, to kick-start replication.

The structure was determined in a collaborative effort between the Bushman lab and the lab of the other senior author Gregory D. Van Duyne, PhD, Professor of Biochemistry and Biophysics and an Investigator with the Howard Hughes Medical Institute (HHMI). Using purified topoisomerase enzyme that had been expressed in bacterial cells, they bound the enzyme to short segments of DNA that contained the viral topoisomerase's specific recognition sequence. They then determined the three-dimensional structure of the topoisomerase-DNA complex using X-ray crystallography.

One of the primary differences between the viral topoisomerase enzyme and the closely related human enzyme that functions in the nucleus of all human cells is that the viral enzyme only relaxes supercoiled DNA when it binds to specific DNA sequences. The structure of the poxvirus topoisomerase-DNA complex provides some important clues about how this recognition and activation mechanism works.

"The more the viral enzyme differs from the human nuclear enzyme, the more likely it is that inhibitors could be developed that are specific to the viral enzymes," says Bushman.

Knowing the three-dimensional structure of the smallpox virus topoisomerase-DNA complex will also facilitate the design of agents to combat poxvirus infections. Topoisomerases are some of the most widely targeted proteins by drugs that are intended to inhibit growth of the cell. Drugs that target topoisomerases generally stabilize an intermediate of the enzyme's reaction in which one of the DNA strands is broken. If these breaks are not repaired, the DNA cannot be replicated and the cell dies.

In the case of smallpox virus, the hope is that drugs targeted to the viral topoisomerase enzyme will prevent viral replication through a similar mechanism. The X-ray structure provides a template for designing small molecules that could stabilize the broken DNA in the intermediate form, thereby killing smallpox virus particles.

Karen Kreeger | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Gene therapy shows promise for treating Niemann-Pick disease type C1
27.10.2016 | NIH/National Human Genome Research Institute

nachricht 'Neighbor maps' reveal the genome's 3-D shape
27.10.2016 | International School of Advanced Studies (SISSA)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

How nanoscience will improve our health and lives in the coming years

27.10.2016 | Materials Sciences

OU-led team discovers rare, newborn tri-star system using ALMA

27.10.2016 | Physics and Astronomy

'Neighbor maps' reveal the genome's 3-D shape

27.10.2016 | Life Sciences

More VideoLinks >>>