Literature Review

Protein of the Month on RCSB

Hemagglutinin (source: PDB protein of the month)

Hemagglutinin is a spike shaped protein that hangs from the surface of the influenza virus. It is composed of two different types of chains, the targeting chains (shown in blue) and the attack chains (shown in yellow). The targeting chains recognize cells based on specific sugar chains extending from the membrane of the cell. When the influenza virus has bound to the cell, the top of the attack chains bind to sugars on sugars on the cell membrane. The virus is then carried inside of the cellular endosome. The cell excretes acid into the endosome, attempting to digest the virus, but instead, the acid induces refolding of the hemagglutinin, causing the hemagglutinin to bind directly to the membrane. The hemagglutinin then opens up the cell membrane and causes the viral membrane to fuse to it. The viral RNA is now free to flow into the cell and infect it.

Structure of Influenza Hemagglutinin in Complex With an Inhibitor of Membrane Fusion

Hemagglutinin is a potential target for for antiviral drugs as it plays a key role in the initial stages of viral infection. Hemagglutinin is an antigenic glycoprotein that allows the influenza virus to bind to cells in order to infect them. It specifically binds to sialic acid on the membrane of cells. Membrane fusion is caused by a drop in the pH, which induces large structural changes in the hemagglutinin.

Structural and Functional Bases for Broad-Spectrum Neutralization of Avian and Human Influenza A Viruses

Influenza evades the bodies natural antibodies due to rapid genetic drift. Monoclonal antibody (mAb) therapy shows promise, The crystal structure of an mAb bound hemagglutinin shows that the heavy chain of the mAb can insert into a highly conserved pocket of the Hemagglutinin stem, and inhibit the conformational changes necessary for influenza to infect the cell. Targeting of this pocket could potentially lead to drugs that can prevent infection by influenza through a cocktail of various neutralizing mAbs that can prevent the acid induced refolding of hemagglutinin.

Computational Design of Proteins Targeting the Conserved Stem Region of Influenza Hemagglutinin

Molecular recognition of hemagglutinin can be achieved through recognition of a conserved pocket on the the stem of hemagglutinin. Antibodies that have been designed to recognize this pocket on H1N1 have been shown to inhibit pH induced refolding in multiple strains of influenza, indicating a novel path for developing drugs that can potentially target multiple strains of influenze at once.

Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift

Hemagglutinin is a rapidly evolving protein that attempts to always stay at least one stop ahead of the human bodies immune system. Influenza evolves by modifying the hemagglutinin sequence, thus affecting the binding of the hemagglutinin to the sialic acid on the surface of the cell. The hemagglutinin proteins that bind more tightly to the sialic acid tag on the outside of the cell membranes are correlated with higher escape from antibodies and thus the viruses carrying them will be more pathogenic.