CD4

3D Structure of CD4 complexed with gp120 and the neutralizing human antibody 17B

CPK Color Scheme C O N P S

This chime image is the protein CD4 complexed with gp120, the HIV viral exterior envelope glycoprotein, and the neutralizing antibody 17B.

Reset to the original view.

You can click here to see the distinct chains that make up this complex.

CD4 is colored in red, gp120 in blue, the heavy chain of the antibody in yellow and the light chain of the antibody in green.

Now let's take a closer look at CD4

CD4 consists of two domains

Domain 1, which consists of residues 1-98 is colored blue and domain 2, which consists of residues 99-181 is colored red. These two domains pack closely against each other so that there is a large common hydrophobic interface. Each domain is an antiparallel beta barrel with the connectivity characteristic of an immunoglobin fold.

Before discussing the interactions between CD4 and gp120, it is important to understand the normal function of CD4 in the immune system. The glycoprotein CD4 is expressed on most thymocytes and on the subset of peripheral T lymphocytes that includes helper T cells, and class II major histocompatibility complex (MHC) specific cytotoxic T cells. MHC Class II is only found on certain other Immune Cells called, Antigen Presenting Cells (APCs). These cells, whether they are B-Cells or Macrophages, or some other Leukocyte, consume foreign proteins (specifically or randomly), and present small portions (Peptides), in conjunction with MHC Class II. It has been shown that amino acid substitutions in domains 1 and 2 of CD4 interfere with functional interactions between CD4 and MHC II molecules. The interactions between CD4 and MHC II molecules are weak, thus, it is difficult to determine the specific residues involved in the interactions. Some studies have indicated that Ser 19

and Glu 89

from domain 1 and Gln 165

from domain 2 play a major role.

Human CD4 is the receptor for the HIV virus. The entry of HIV into cells requires the sequential interaction of gp120 with CD4 and a chemokine receptor on the T-cell surface. Direct interatomic contacts are made between 22 CD4 residues and 26 gp120 amino-acid residues. Phe 43

is one of the most important residues on CD4 because the exposed aromatic ring makes contact with the gp120 molecule.

The residues Lys 29, Lys 35, Lys 46, and Arg 59 are positively charged amino acids that have an effect on gp120 binding and partly surround the Phe 43 on the molecular surface.

Now let's take a look at the interaction between gp120 and these 5 residues on the CD4 molecule.

The most important residues for binding on gp120 are Asp368, Glu 370 and Trp 427.

These residues are colored in white.

Let's zoom out on this image and see how the whole CD4, gp120 complex fits together.

Let's examine the structure of the gp120 core molecule.

The left side of the molecule is the inner domain and the right side of the molecule is the outer domain. The portion of the structure that links the innter domain and the outer domain is known as the bridging sheet. The gp120 core comprises 25 beta strands (orange), 5 alpha helices (pink), and 10 defined loop segments (white). As seen

the residues that bind to CD4, colored in green, are located within the bridging sheet portion of the molecule.

The 17B antibody is broadly neutralizing monoclonal antibody isolated from the blood of an HIV infected individual. It binds to a CD4 induced gp120 epitope. The 17B contact surface is very acidic although hydrophobic contacts are predominate in the center. On gp120, the 17B epitope lies across the base of the four-stranded bridging sheet. The gp120 surface that contacts the antibody is basic which complements the acidic 17B surface. Let's look at how the antibody binds to gp120.

The heavy chain, colored in yellow, dominates the antibody interaction with gp120, although the light chain, colored in green participates as well. Within this interaction there is only one salt bridge formed between Arg419 of gp120 and and Glu 106 of the 17B heavy chain.

To return to the original view click here:

References:

Kwong, P.D. et. al. 1998. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393: 648-659.

Wang, J. et. al. 1990. Atomic Structure of a gragment of human CD4 containing two immunoglobin-like domains. Nature 348: 411-418.

Wyatt, R. et. al. 1998. Structure of the Core of the HIV-1 gp120 Exterior Envelope Glycoprotein. Analyses III: 3-9.

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This page was produced as an assignment for an undergraduate course at Davidson College.
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