Structural Studies of Molecules Involved 
in the Immune Recognition of Infected Cells 
Pamela J. Bjorkman, Ph.D. — Assistant Investigator 
Dr. Bjorkman is also Assistant Professor in the Division of Biology at the California Institute of 
Technology and Adjunct Professor of Biochemistry at the University of Southern California School of 
Medicine, Los Angeles. She received a B.A. degree in chemistry from the University of Oregon and a Ph.D. 
degree in biochemistry and molecular biology from Harvard University, where her thesis advisor was Don 
Wiley. She completed a low-resolution structure of a human histocompatibility molecule for her thesis 
and then stayed on to finish the work. She continued her postdoctoral training at Stanford University in 
the laboratory of Mark Davis before joining the staff at Caltech. Dr. Bjorkman received the William B. 
Coley Award for Distinguished Research in Fundamental Immunology from the Cancer Research Institute. 
THE technique of x-ray crystallography allows 
visualization of the three-dimensional struc- 
tures of proteins in atomic detail. In other words, 
we get a picture of the protein that shows the 
location of all the atoms and how they interact. 
The shape of a protein and the location of individ- 
ual atoms with respect to one another are impor- 
tant for determining how the protein functions. 
With such knowledge it is often possible to de- 
sign compounds that modify the protein for medi- 
cal intervention. 
The proteins that we are studying structurally 
are those that mediate the immune response 
against viruses and other pathogens. The immune 
system has evolved so that highly specific mole- 
cules on the surfaces of lymphocytes can recog- 
nize a virally infected cell. In the infected cell, 
pieces of viral proteins are fragmented and bound 
to a cellular protein called a histocompatibility 
molecule. If the complex formed between the 
histocompatibility molecule and the viral frag- 
ment is recognized by a protein on the lympho- 
cyte, the infected cell is destroyed. The lympho- 
cytes that bear the recognizing proteins are T 
cells, and the proteins on their surface are T cell 
receptors. 
The three-dimensional structure of a histocom- 
patibility protein gives us a picture of how and 
where viral molecules bind and how T cell recep- 
tors might bind to the complex formed between 
the viral and histocompatibility molecules. My 
laboratory now seeks to determine a three- 
dimensional structure for a T cell receptor, in 
order to understand the atomic details of its inter- 
action with the surface of an infected cell. (This 
work is being done in collaboration with Mark 
Davis, HHMI, Stanford University.) We have crys- 
tallized a T cell receptor and now seek to make 
crystals of a complex between a T cell receptor 
and histocompatibility molecule. An understand- 
ing of how T cell receptors interact with histo- 
compatibility molecules complexed to viral frag- 
ments should increase our understanding of how 
the immune system distinguishes normal, healthy 
cells from virally infected cells that need to be 
destroyed. 
Our laboratory is also using protein expression 
systems in mammalian and bacterial cells to pro- 
duce the large quantities of proteins necessary for 
crystallization and structural studies. Using mo- 
lecular biological techniques, it is possible to 
transfect a protein-encoding gene into a cell in 
which it is not normally found, thus persuading 
that cell to manufacture that protein. Many pro- 
teins normally occur in small quantities; the use 
of such protein expression systems allows the 
isolation of much more of the protein than would 
be otherwise possible. We have expressed histo- 
compatibility proteins in bacteria and formed 
complexes between these proteins and antigenic 
peptides. 
We have also used a similar system to make an 
Fc receptor, a protein that binds to the Fc portion 
of antibody molecules. This particular Fc recep- 
tor is found in the intestine of newborn mammals 
and binds immunoglobulin found in mother's 
milk, thus transferring partial immunity from 
mother to infant. The amino acid sequence and 
structural organization of this molecule show sim- 
ilarities to histocompatibility molecules. We 
have made a soluble (non-membrane-bound) 
version of this molecule, which is still capable of 
binding to Fc molecules. We have recently puri- 
fied and crystallized this Fc receptor and initiated 
a three-dimensional structure determination. We 
have also crystallized a complex between the re- 
ceptor and the Fc portion of an antibody; this will 
ultimately allow us to obtain a picture of how the 
two proteins interact. A comparison of the Fc re- 
ceptor structure and its interaction with antibod- 
ies should increase our understanding of the 
structurally related histocompatibility proteins 
and perhaps reveal reasons for the evolution of 
this type of structure in the immune system. We 
also have crystals of a structurally unrelated Fc 
receptor and are interested in comparing how the 
two types of receptors bind to their common 
ligand. 
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