Structure of HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing antibody

The entry of the HIV virus into cells requires the sequential interactions of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. These interactions initiate a fusion of the viral and cellular membranes.

Cartoon Structure Complex of gp120 (blue) and CD4 (green)

Bound form gp120

The residues that are critical for binding are Phe43 (yellow) and Arg59 (yellow) for CD4, which interact with Asp368 (purple), Glu370(purple), and Trp427 (purple) of gp120:

Important Contacts between gp120 and CD4

Before these important interactions occur the gp120 is in an unbound form which is significantly different from the bound form. To the naked eye, the unbound form appears very similar to the bound form.

Unbound form gp120

However, when comparative analysis is attempted, the significant conformational differences become clear as Deep View is unable to overlay the two forms:

Merged Unbound and Bound form gp120 - backbone

Merged Unbound and Bound form gp120 - cartoon

From the cartoon it is clear that the only regions the Deep View program could line up were the alpha-helices on one side. In addition to the significant conformational changes that occur when gp120 binds to CD4, this mismatch could be due to the fact that the template used for the unbound form is the simian immunodeficiency virus gp120 core (SIV). In contrast, the template for the bound form is the human immunodeficiency virus gp120 core (HIV) . While many properties are retained, the differences make it hard for a program to overlay the glycoproteins.

- Antibody Binding -

The conformational change that occurs when gp120 binds to CD4 forms exposes a binding site for specific chemokine receptors. The Fab 17b antibody (yellow) binds to the CD4-bound gp120 and overlaps the chemokine receptor binding site:

Cartoon Structure Complex of gp120, CD4, and Fab 17b

Visualization of the interactions between the HIV gp120 glycoprotein envelope and the CD4 receptor with a neutralizing human antibody (Fab 17b) gives possible clues into ways to prevent HIV entry into cells. The glycosylation, oligomeric occlusion, and conformational changes in the core gp120 provide the mechanisms for evading the immune system. An effective vaccine may be developed based on the understanding of how HIV evades the immune system. If successfully developed, this vaccine could save countless lives.

 

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