Structural Studies of DNA-hinding Proteins 
Tools for Analyzing Protein-DNA 
Interactions 
We are working on several other projects that 
should help to develop the background for a sys- 
tematic analysis of protein-DNA interactions. 
Because structural analysis often is limited by 
the ability to obtain suitable crystals, w^e are try- 
ing to improve methods for the cocrystallization 
of protein-DNA complexes. Our initial approach 
involved systematic changes in the length of the 
DNA site and required that the entire site be re- 
synthesized for each experiment. We now have 
encouraging preliminary results with a linker co- 
crystallization scheme that combines the protein, 
the binding site, and a library of DNA linkers that 
can be used with any complex. This strategy may 
allow a dramatic increase in the number of co- 
crystallization conditions that can be tested. 
We have also been developing testing strate- 
gies for computer-aided protein design. Our pro- 
grams can systematically consider a large number 
of sequences and conformations, and we are us- 
ing these programs as we attempt to design zinc 
finger proteins that will recognize novel binding 
sites. We also are developing genetic strategies 
for selecting zinc finger proteins that recognize 
desired target sequences. We hope that this com- 
bination of structural analysis, computer-aided 
protein design, and genetic selection will give us 
a better understanding of protein-DNA recogni- 
tion and allow us to design zinc finger proteins 
that recognize novel target sites. 
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