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BIOLOGICAL CHEMISTRY
Researchers Glimpse Poliovirus as It Enters Host CellImages Could Shed Light on More Intractable BugsA team of researchers at HMS and other institutions has produced the first 3-D structures—the biological equivalent of snapshots—of the poliovirus in the moments after it attaches to and enters a host cell. The structures, which appear in the February Journal of Virology, follow on the heels of a molecular rendering by the same team of the virus attaching to the host cell receptor. The virusŠreceptor complex was published in the Jan. 6 Proceedings of the National Academy of Sciences. Though poliovirus has yielded to medical know-how—vaccination programs have eradicated it from the West and promise to eliminate it globally—it has proved to be a stubborn subject for scientists. Surprisingly little is known about how poliovirus enters host cells. Some have suspected that after attaching to the host, the virus changes its shape, producing two intermediate forms. James Hogle and colleagues at HMS and the National Institutes of Health have determined the structure of these forms using a powerful combination of techniques—cryoelectron microscopy and X-ray crystallography.
Jim Hogle (left) compares his poliovirus structures to "snapshots along the viral entry pathway." With him is David Filman, lecturer in biological chemistry and molecular pharmacology, who worked on all the structures. Hogle, who is the Edward S. Harkness professor of biological chemistry and molecular pharmacology, and his colleagues have interpreted the images, together with the receptorŠvirus structure, to tell a story of an extremely dynamic particle. From the moment it attaches to its host, the poliovirus appears to make adjustments in its protein shell that allow it to grab onto its host receptor more tightly. The virus creates temporary openings in its shell through which it tosses tiny protein threads that embed in the host cell membrane, not only anchoring the virus to the cell but possibly creating pores for the viral RNA to enter. The story could be similar for a range of viruses that together cause a variety of effects including encephalitis, paralysis, diabetes, and heart ailments. Though they use different receptors, the bugs' primary process of infection is similar to that of poliovirus. "Understanding these viruses gives you a route to potentially making drugs to thwart them," Hogle says.
Structural modeling requires some interpretation, as suggested by this rendering of the virus–receptor complex (top right) by Jim Hogle, working with the NIH's Alasdair Steven, Columbia University's Vincent Racaniello, and colleagues. The model appears back-to-back in the Jan. 6 Proceedings of the National Academy of Sciences with one by a team from Purdue (not shown). On the face of it, both structures depict a mottled sphere, the virus, studded with 60 twiglike structures, the receptors, each of which is buried deep in a canyon on the viral surface. But the two groups differ in the way they orient the receptor at the point where it burrows into the virus (Domain 1 in illustration). The discrepancy hints at an even deeper difference in interpretation. The Purdue group believes that the receptor binding sites are buried deep in the canyons in order to make them inaccessible to antibodies. Hogle and his colleagues believe that the receptor, in addition to binding the virus, induces the virus to undergo its conformational change into the 135S form by donating energy. "Binding deep in a pocket, or invagination, is an efficient way to increase surface area and therefore energy," Hogle says. In fact, the virus, to maximize this transfer of energy, may make small movements in its shell. "There's some evidence that tight binding requires adaptations by the virus to the receptor," Hogle says. "So there's probably an accommodation going on in the virus." |
