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Herpes viruses cause several incurable diseases. They infect cells by fusing viral and cellular membranes. Now, X-ray studies have revealed the unusual structure of a key protein complex that allows a herpes virus to invade cells. There are eight herpes viruses that cause human diseases. Depending on how they affect us, they result in oral and genital herpes, the latter of which is present in almost a third of the US population. Currently, there is no cure for herpes viruses. Upon infection, the viruses remain in the body for life and can stay inactive for long periods of time. Herpes is also a leading cause of viral blindness and viral encephalitis. In addition, the cytomegalovirus (CMV), one of the herpes virus family, leads to organ transplant rejection after surgery while varicella-zoster virus causes chicken pox in children and shingles in adults. Other relatives include the Epstein-Barr virus that causes Burkitt's lymphoma and Kaposi's sarcoma virus as well as another that causes cold sores. "What we have here are troubling, even lethal afflictions, all bundled in one nasty package, poised and waiting to do harm, explains Gary Cohen, a biologist at the University of Pennsylvania who is collaborating with crystallographer Ekaterina "Katya" Heldwein and Tirumala Chowdary of the Department of Molecular Biology and Microbiology, at Tufts University School of Medicine, in Boston, Massachusetts. There is a ray of medical hope, of course, a virus has to gain access to our cells to cause infection, and so understanding the precise entry mechanism could offer medicinal chemists a target. One might assume that we would already know all there is to know about such a common and familiar family of viruses, unfortunately, explains Heldwein, who began her work on herpes at Harvard, even the experts don't have answers to the basic questions about the virus. For instance, little is known about the four glycoproteins that work together to allow the virus to gain entry into a cell. Moreover, even less is known about how they work together. The team explains that whereas most other enveloped viruses use a single viral catalyst called a fusogen, herpes viruses, inexplicably, require two conserved fusion-machinery components, gB and the heterodimer gH-gL, plus other components that are not conserved. Moreover, gB is a class III viral fusogen but, inexplicably, requires gH-gL to function. Now, Heldwein and colleagues have used the synchrotron X-ray source at the Argonne National Laboratory, near Chicago, Illinois, to obtain diffraction images from crystals of the heterodimer gH-gL. "We determined the crystal structure of the gH ectodomain bound to gL from herpes simplex virus 2," the team explains, "gH-gL is an unusually tight complex with a unique architecture that, unexpectedly, does not resemble any known viral fusogen. Instead, we propose that gH-gL activates gB for fusion, possibly through direct binding". "It looks like a boot and sort of 'kicks' the fusion protein into action," Heldwein adds. "It acts like the 'mover and shaker' of gB". Heldwein and colleagues propose that "formation of a gB-gH-gL complex is critical for fusion and is inhibited by a neutralizing antibody, making the gB-gH-gL interface a promising antiviral target." With the X-ray data in hand and structures determined, they are now trying to figure out how the fascinating foursome work. Alongside Tufts' Chowdary and Pennsylvania biologist, Cohen, Heldwein is working with Tina Cairns, Doina Atanasiu, and Roselyn Eisenberg. "Now we need to understand how they work together," explains Heldwein. "Why are there four? We don't know. We can speculate, but we don't know," she says. "We hope that determining the structure of this essential piece of the herpes virus cell-entry machinery will help us answer some of the many questions about how herpes virus initiates infection. Knowing the structures of cell-entry proteins will help us find the best strategy for interfering with this pervasive family of viruses," adds Chowdary, who is a postdoctoral associate in the department of molecular biology and microbiology at TUSM and a member of Heldwein's research group.
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Herpes simplex cell-entry protein |
