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Neuraminidase

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The flu virus is constantly evolving, every year we hear of new strains, in fact, every decade or so, a new strain is dangerous and poses a threat to public health. Last year, there was an outbreak of a new strain of flu virus, the '
H1N1, more commonly known as swine flu virus. The name H1N1 refers to two types of molecules that coat the surface of the virus: hemagglutinin
and neuraminidase . Together, these two molecules determines the infectivity of the virus. The hemagglutinin plays a decisive role when the virus approaches the cell by binding to the polysaccharide chains on the cell surface and then injecting the
viral DNA into the cell. The neuraminidase, on the other hand, comes into play when the virus leaves the infected cells. Ensures that the virus does not remain bound to the surface polysaccharides of cutting their chains.

Cut sugars

The neuraminidase, shown above from the PDB file 1nn2, consists of four identical subunits arranged a square. It is normally linked to the virus surface protein with a long arm, not shown. The active sites are located in deep depressions of the surface above, bind to cellular polysaccharide chains and cut the sugar terminal. The surface of the neuraminidase has linked some of the chains of polysaccharides in the structure above, we see extend upwards and downwards, and are similar to the polysaccharide chains present on the surface proteins of our cells.

Pigs and people

As the hemagglutinin, neuraminidase, even if there are several sittotipi known as N1-N9. These subtypes are defined by their interaction with antibodies: all variants of the same subtype are neutralized by the same type of antibodies. These subtypes are one of the causes of the continued aggression of influenza. Some subtypes can infect people, infect other birds and others can attack the pigs or other mammals. When different viruses infect the same body, the various subtypes can be mixed and combined in different ways, giving rise to new random combinations that occasionally can be particularly dangerous or even fatal, thus leading to the formation of new strains

. fight the flu are two most effective drugs currently in use to fight the flu: zanamivir (Relenza) and oseltamivir (Tamiflu). These drugs have been discovered using crystal structures taken from PDB files. By studying the binding of various molecules with the active site of neuraminidase, the researchers were able to design new drugs that mimic the natural substrates of the enzyme. These molecules bind strongly in the active site and block the action that is essential for the release of virus from the cell membrane. Here are shown two structures of these drugs. the middle, PDB file 3b7e, zanamivir is shown (blue) linked to the English influenza virus neuraminidase that caused a pandemic in 1918. Below, PDB file 2hu4, oseltamivir is shown (blue) linked to the avian influenza virus neuraminidase.

Antibodies and vaccines When we get sick of influence, our immune system produces antibodies to fight the virus.
An influenza vaccine can prepare your immune system for this protective action by putting it in contact with a weakened virus or harmless fragments of the virus. In this way the vaccine makes the immune system to produce the right antibodies before infection occurs itself. antibodies recognize proteins on the surface of the virus. antibodies most effective are those that attack the hemagglutinin and thus block the infection of new cells.
antibodies against neuraminidase, such as those shown here in blue, the image comes from the PDB file 1NCA can make it lighter than the flu, and they too help to fight the virus.

explore the structure
To design a drug that could cure people should pay close attention. drugs should be different from the natural substrate of the enzyme so that the enzyme can not catalyze the reaction to destroy them. the same time, the drugs must be very similar to the natural substrate of the enzyme to bind strongly to the active site to block it. It 'also important that medications are similar to natural substrates to avoid drug resistance. An example of this problem is illustrated in three figures below The first figure shows the neuraminidase bound sialic acid in its active site, PDB file
2bat
. This figure shows the normal interaction of the enzyme with a polysaccharide, its natural substrate. The second figure shows the link with oseltamivir, a drug used to combat influenza, 2hu4 PDB file. Note that this is similar but not identical sialic acid. E 'slightly larger forces and a glutamic acid (pink) to bend a little' to the histidine on him (also pink). The third figure shows a variant of the enzyme who developed drug resistance, 3cl0 PDB file. In this mutant enzyme, histidine has been replaced by a tyrosine (Tyr274 pink), being larger, glutamic acid leads down to the drug. Oseltamivir can still bind, but in a less strong due to interference with glutamic acid (pink) and thus can be ousted out of the polysaccharide, the natural substrate. The drug is therefore ineffective in combating the virus mutant. However, there is still enough space to bind sialic acid, and then the mutant enzyme still functions to perform its normal action release of the virus.

Sources:
PDB