Structure of a Designed Dimeric Zinc Finger Protein Bound to DNA,

Biochemistry, 42 (46), 13401 -13409, 2003. 10.1021/bi034830b S0006-2960(03)04830-X
Web Release Date: October 30, 2003

Structure of a Designed Dimeric Zinc Finger Protein Bound to DNA

Scot A. Wolfe,* Robert A. Grant, and Carl O. Pabo

Department of Biology and the Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Received May 19, 2003

Revised Manuscript Received September 22, 2003

Abstract:

Proteins that employ dimerization domains to bind cooperatively to DNA have a number of potential advantages over monomers with regards to gene regulation. Using a combination of structure-based design and phage display, a dimeric Cys₂His₂ zinc finger protein has been created that binds cooperatively to DNA via an attached leucine zipper dimerization domain. This chimera, derived from components of Zif268 and GCN4, displayed excellent DNA-binding specificity, and we now report the 1.5 Å resolution cocrystal structure of the Zif268-GCN4 homodimer bound to DNA. This structure shows how phage display has annealed the DNA binding and dimerization domains into a single functional unit. Moreover, this chimera provides a potential platform for the creation heterodimeric zinc finger proteins that can regulate a desired target gene through cooperative DNA recognition.

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