Ev71 virus structure

Department of Biological Sciences, Purdue University. Download image. The virus, called enterovirus 71, causes hand, foot and mouth disease, and is common throughout the world. Although that disease usually is not fatal, the virus has been reported to cause encephalitis, a potentially fatal illness found primarily in the Asia-Pacific region. Now, two research teams are reporting new findings about the structure of the virus.

One of the teams, from Purdue University, has proposed a way to design antiviral drugs to treat the infection. Findings from that team are detailed in a paper appearing Thursday March 1 in the online Express issue of the journal Science.

Both teams used a technique called X-ray crystallography to determine the virus's precise structure, showing similarities to features on related enteroviruses, including poliovirus. However, a key feature is different in that a small molecule called a "pocket factor," located within a pocket of the protective shell of the virus, is partially exposed in EV When the virus binds to a human cell, the pocket factor is squeezed out of its pocket resulting in the destabilization of the virus particle, which then disintegrates and releases its genetic material to infect the cell and replicate.

Researchers led by Rossmann have developed antiviral drugs for other enteroviruses such as rhinoviruses that cause the common cold. The drugs work by replacing the pocket factor with a molecule that binds more tightly than the real pocket factor. This hinders infection in two ways: The drug molecule fills the pocket, making it difficult for a virus to bind to a human cell.

Also, because the drug binds tightly to the pocket, it stabilizes the virus and keeps it from disintegrating and releasing its genetic material into the host cell.

However, in enterovirus 71 - or EV71 - a portion of the pocket factor sticks out of the pocket, exposing a hydrophilic tip, whereas the pocket factors in other related viruses are entirely enclosed in the pocket. In order to hinder EV71 infection, antiviral drugs must have a hydrophilic tip at one end to mimic the pocket factor.

Our structural and mutagenesis study demonstrated that both the negative charging and the correct positioning of the C-terminus are essential for EV71 replication. Deletion of the "LLWL" motif abrogated the proteolytic activity, indicating that the motif is critical for maintaining the active proteinase conformation. Our findings provide the structural and functional insights into EV71 2A pro and establish a framework for structure-based inhibitor design.

Keywords: chymotrypsin-like proteinase; enterovirus 71; innate immunity evasion; virus replication; zinc binding site. Abstract EV71 is responsible for several epidemics worldwide; however, the effective antiviral drug is unavailable to date.