Structural Basis of Interactions Within and Between Macromolecules 
be very mobile, whereas the a-helix dipoles are 
locaHzed during the folding of the protein. 
The effectiveness of the a-helix dipole in con- 
tributing to protein stability is a verification of 
our earlier results. Such studies are indicating 
ways in which the stabilities of proteins might be 
improved by genetic engineering. We hope to be 
able eventually to stabilize biological molecules 
used in medicine, such as vaccines, and to im- 
prove enzymes that are used in the pharmaceuti- 
cal and food industries. 
Receptor-Ligand Interaction 
To develop an understanding of the mode of 
action of growth factors and their interactions 
with their receptors, we have crystallized and de- 
termined the high-resolution structure of human 
fibroblast growth factor. The structure was found 
to be very similar to that of interleukin-ljS. It 
seems clear that many growth factors have similar 
overall structures, but the exact relationship of 
these factors in the vicinity of their receptor- 
binding regions remains to be clarified. 
Protein-DNA Interaction 
We have been interested for some time in the 
interaction between proteins and nucleic acids. 
In 1981 we determined the structure of the Cro 
repressor protein of bacteriophage X (bacteria- 
infecting virus) . Cro has served as one of the pro- 
totypical examples of a DNA-interacting protein. 
This small dimeric protein recognizes and binds 
to a specific set of 17 base pairs on the phage 
genome. 
The structure of Cro, as determined crystallo- 
graphically, suggested that a characteristic part of 
the protein, now known as the helix-tum-helix 
motif, is especially important in DNA binding. 
The helix-tum-helix unit can be considered as a 
"reading head" that fits into the grooves of the 
DNA and matches the DNA structure at the spe- 
cific recognition site. It is now known to occur in 
a large number of DNA-binding proteins, and its 
functional role has been confirmed by structures 
of several DNA- protein complexes. 
Recently we have determined the crystal struc- 
ture of Cro protein in complex with a tight-bind- 
ing, 1 7-base pair DNA operator. We are improv- 
ing the accuracy of the structure by a process of 
crystallographic refinement. In general terms the 
structure of the complex supports the model for 
Cro-DNA interaction that was proposed on the 
basis of the uncomplexed protein. 
The Cro dimer, however, undergoes a substan- 
tial conformational change relative to the un- 
complexed crystal structure. One monomer ro- 
tates relative to the other by about 45°. This 
supports the idea that the Cro dimer is very flexi- 
ble in solution. The DNA maintains an essentially 
Watson-Crick conformation, but is bent in the 
middle of the operator into the shape of a shallow 
boomerang. 
We have recently obtained high-quality crys- 
tals of the biotin repressor from Escherichia coli. 
Determination of the structure of this more com- 
plicated protein, which not only binds DNA but 
also acts as an enzyme, is well under way. 
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