Basic IgG structure
This is a schematic cartoon of an IgG molecule showing some of the
features of the molecule including the flexibility of the Fab and Fc
regions. This schematic can be compared with the other images shown here
which have been rendered from crystal structures of the fragments of Ig
molecules.
Immunoglobulin Structures
A complete resolved structure for a human immunoglobulin molecule has only
recently been determined. A structure for a whole mouse
IgG2a molecule was the first complete immunoglobulin molecule to have been
solved. It is surprising to some just how few solved immunoglobulin
structures for different species and isotypes of immunoglobulins there are
in the database. For practical as well as academic and also commercial
reasons many researchers have concentrated their studies on determining the
structures of immunoglobulin Fabs and perhaps not surprisingly on their
interactions with antigen. Additionaly the interaction of immunoglobulin Fc
and Fab regions with bacterial ligands such as Protein A and Protein G have
been studied. The models of human IgG1 shown here have in fact been
generated by combining several structures in one model and it should be
noted and can be seen in the models that the hinge region joining the heavy
chain CH1 and CH2 domains is missing. The structures
shown here are of a simulated whole IgG1 , the Fc region and the Fab region.
Details of how the model was generated are also
given.
This is a raytraced image of the model of human IgG1 showing the two
heavy chains in red, the two light chains in yellow and the carbohydrate
attached to the heavy chains in purple. The rotational symmetry about a
vertical axis can be clearly seen in this picture.
This is a cartoon representation of the same model in which the
secondary structure of the alpha-carbon backbone trace is shown. The beta
strands are indicated as ribbons and can be clearly seen. Note how most of
the domains within the structure have one face in intimate contact with a
second domain. Thus the heavy and light chain V-region domains are in
contact, as are the light chain C region domain and heavy chain CH1 domain,
and the two heavy chain CH3 domains. However note the separation of the two
heavy chain CH2 domains in the middle of the structure. Evidence suggest
that it is the CH2 domains that are of primary importance in determining Fc
effector functions such as complement activation (C1q binding) and Fc
Receptor (Fc gamma R) binding. However other parts of the molecule may also
be critical, in particular the hinge region and hinge link or lower hinge
region (where the genetic hinge joins on to a part of the hinge encoded
genetically as the N-terminal end of the CH2 domain).
This is a cartoon of the same model of human IgG1 in which the
secondary structure within the model is indicated by both shape and colour.
The conserved beta barrel structures making up each immunoglobulin domain
along with the beta turns and helical turns at the ends of the beta strands
can clearly be identified. If you look carefully you will see that the
domain structures for the heavy and light chain V-regions is different from
the constant region domains.
This shows a larger view of the secondary structure cartoon of the Fc region from the
model. This is based on the alpha carbon trace of the heavy chain and so the
carbohydrate which lies between the two CH2 domains cannot be seen. Note the
close association of the two CH3 domains.
In this cartoon the two heavy chains have been coloured in red and blue
which makes it much easier to see the contact between the two CH3 domains
and if you take a look at the structure below which is rotated you will get
an even better idea of the contact.
Is the same cartoon structure as above but rotated through 90 degrees
about a vertical axis showing from a different viewpoint the contact between
CH3 domains. Compare the two views and also take a look at the heavy light
chain interactions in the Fab structure.
This shows a larger view of a secondary structure cartoon of a single
Fab arm from the model which has been coloured according to secondary
structure. The contact between V regions and C regions can be clearly seen.
The "elbow" bend in the molecule can be made out from the apparent gap in
the structure leading from the V-region domains to the C-region domains,
joined by a single amino acid strand for each chain. At the bottom left of
the structure you can see where the heavy chain would join on to the hinge
region.
Is a cartoon of the other Fab (ie rotated through 180 degrees from the
structure above) in which the heavy chain is shown in red and the light
chain is a paler colour.
For the models of human IgG1 shown here I took the coordinates for a crystal
structure of a Fab fragment of human IgG1 and a second structure of human
IgG1 Fc fragment. The images of a whole antibody are in fact attempts to
reconstruct a complete structure from the individual fragments. Firstly I
took a structure for a human Fab fragment and cloned it to give two
identical copies. One of these copies was then rotated through 180 degrees
to simulate a second Fab arm. Then these two Fabs were combined together
along with a structure of a human IgG1 Fc fragment to give the appearance
of a whole IgG. However the structure of the hinge region has not been
determined, presumably because of it's flexible nature, and so this is not
shown in the models! The following image shows more clearly the component
segments which make up the whole model. The two chains of the Fc, and the
four chains making up the two Fab arms, as well as the two chains of
carbohydrate, each attached to one of the heavy chains in the Fc fragment,
are all coloured separately.
This shows a representation of the model of Human IgG1 showing the
different segments which go to make up the model in different colours.
Here is raytraced image of the same model of Human IgG1 which gives a
better 3D representation to the viewer of a static image. Note the two
chains of carbohydrate attached to a conserved site in the CH2. These
carbohydrate chains are found within the gap between the two CH2 domains in
the structure.
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This page is from
Mike Clark
"An antibody engineer who also enjoys the mountains."
mrc7@cam.ac.uk
Mike's home-page"
10th October 2003