Siendo más astuto a los trucos del virus de la influenzaContributed by: AdminStaff1 · Views: 1,353
Contributed by: AdminStaff1 · May 05, 2008 @ 03:40 PM MDT · Views: 1,353
Getting wise to the influenza virus' tricksA high-resolution image of an influenza virus protein opens the way to design new antiviral drugs
The high-resolution image of the influenza virus' PB2 protein
shows how the virus steals a 'cap' molecule from its host to take
over the protein production machinery and multiply. PB2 binds the
cap [purple] by sandwiching it between aromatic amino acids.
Upon infection the influenza virus starts multiplying in the cells of its host. One protein that is crucial in this process is the viral polymerase - the enzyme that copies its genetic material and helps to produce more viruses. One component of the polymerase, called PB2, plays a key role in stealing an important tag from host cell RNA molecules to direct the protein production machinery towards the synthesis of viral proteins. Researchers of the groups of Stephen Cusack and Darren Hart at EMBL Grenoble have identified the PB2 domain responsible for binding the tag, produced crystals of it and examined them with the powerful X-ray beams of the European Synchrotron Radiation Facility [ESRF].
"Viruses are masters of cunning when it comes to hijacking the normal functioning of the host cell. The influenza virus steals a password from host messenger RNAs, molecules that carry the instructions for protein production, and uses it to gain access to the cell's protein-making machinery for its own purposes," says Cusack.
The password is a short extra piece of RNA, a modified RNA base called a 'cap', which must be present at the beginning of all messenger RNAs [mRNAs] to direct the cell's protein-synthesis machinery to the starting point. The viral polymerase binds to host cell mRNA via its cap, cuts the cap off and adds it to the beginning of its own mRNA – a process known as 'cap snatching'. The capped viral mRNA can then be recognised by the host cell machinery allowing viral proteins to be made, at the expense of host cell proteins.
The atomic resolution image the EMBL scientists generated of a PB2 domain bound to a cap reveals for the first time the individual amino acids responsible for recognising this special structure. The central interaction is a sandwich with two PB2 amino acids stacking either side of the cap. Whilst this recognition mechanism is similar to other cap-binding proteins, its structural details are distinct. Collaborators at the Centro Nacional de Biotecnologia in Madrid showed that disruption of the PB2 cap-binding site prevents the influenza virus from replicating.
"These findings suggest that the PB2 cap-binding site is a very promising target for anti-influenza drugs," Hart says. "Our new structural insights will help us design mimics of the cap that would inhibit viral replication and hence reduce the spread of virus and the severity of the infection."
D. Guilligay, F. Tarendeau, P. Resa-Infante, R. Coloma, T. Crepin, P. Seh, J. Lewis, R. Ruigrok, J. Ortin, D. Hart & S. Cusack. The structural basis for cap-binding by influenza virus polymerase subunit PB2. Nature Structural and Molecular Biology, 4 May 2008
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Source: European Molecular Biology Laboratory (EMBL)