Neuraminidase is a surface protein found on various viruses, notably influenza viruses. It functions as an enzyme encoded by the virus’s genetic material and is one of the main proteins that stud the viral surface. Its presence and type are used to classify certain influenza strains, such as in the H1N1 designation.
The Overall Architecture of Neuraminidase
The neuraminidase protein has a distinct mushroom-like shape that projects from the surface of the virus. This structure is a tetramer, meaning it is assembled from four identical protein subunits arranged in a square. This assembly is anchored into the outer lipid membrane of the virus particle. The complete structure can be divided into four domains: a cytoplasmic tail, a transmembrane region, a stalk, and a large head domain.
The stalk connects the functional head of the protein to the virus particle, and its length can vary to correctly position the head. Most of the protein’s mass is in the large, globular head that extends away from the viral surface. This head is characterized by a six-bladed propeller fold for each subunit, creating a stable outer structure.
The four subunits are held together tightly to form the functional tetramer. Disulfide bonds, which are strong chemical links between specific amino acids, are important for stabilizing the individual subunits and the overall complex. The arrangement of these four heads creates a square-shaped structure when viewed from above, with a channel at the center of the tetramer.
The Catalytic Active Site
Located on the top surface of each of the four globular head domains is a deep cleft. This pocket is the catalytic active site where the enzyme’s chemical reaction takes place. Because neuraminidase is a tetramer, each complete protein possesses four of these active sites, one on each subunit. The structure and amino acid composition of this site are highly conserved across different influenza virus subtypes.
This conservation indicates the functional importance of the site’s precise geometry. The pocket is formed by a specific arrangement of amino acid residues that line its surface. These residues create a chemical environment suited to bind to its target molecule, sialic acid. For example, a trio of arginine residues creates a positively charged area to attract the negatively charged target.
Other residues, including glutamate and tyrosine, are positioned to perform the chemical cleavage. The rigidity and specific shape of this pocket are maintained by the surrounding protein structure. This stable architecture ensures that the enzyme can function efficiently.
Structural Importance in Viral Release
The primary function of neuraminidase is to facilitate the release of new virus particles from an infected host cell. When new virions are assembled, they emerge from the cell surface but can remain tethered. This is because another viral protein, hemagglutinin, binds to sialic acid residues on the host cell and the virus particles, causing them to stick.
Neuraminidase acts as molecular scissors, and its active site is shaped to bind to these terminal sialic acid residues. Once the sialic acid enters the active site, the enzyme catalyzes a reaction that cleaves the bond connecting it to the sugar chain. This action destroys the receptor that holds the virus in place, cutting the new virions free.
By severing the connection to the host cell, neuraminidase allows the newly produced virus particles to detach and spread to infect neighboring cells. The enzyme also removes sialic acid from the surface of the virus itself. This prevents the particles from clumping together and ensures they can disperse effectively.
Exploiting the Structure for Antiviral Drugs
The conserved and specific structure of the neuraminidase active site makes it an ideal target for antiviral drug development. Scientists have designed molecules that mimic sialic acid but with modifications that cause them to bind more tightly within the catalytic pocket. These drugs are known as neuraminidase inhibitors.
Drugs like oseltamivir and zanamivir are shaped to fit snugly into the active site, acting as a plug. They form strong interactions with the amino acid residues that line the pocket. By occupying the active site, these inhibitors prevent the enzyme from binding to and cleaving sialic acid.
With its neuraminidase function inhibited, the virus cannot sever its connection to the host cell. As a result, newly formed virions remain tethered to the cell surface. This prevents them from being released to spread the infection, halting the propagation of the virus within the body.