Segments of protein that do not adopt a well-ordered conformation in the absence of DNA can still contribute to site-specific recognition of DNA. The first six residues (NH2-Ser1-Tbr2-Lys 3-Lys4-Lys5-Pro6-) of phage A repressor are flexible but are important for site-specific binding. Low-temperature x-ray crystallography and codon-directed saturation mutagenesis were used to study the role of this segment. All of the functional sequences have the form [X]1-[X]2-[Lys or Arg]3-[Lys] 4-[Lys or Arg]5-[X]6. A high-resolution (1.8 angstrom) crystal structure shows that Lys3 and Lys4 each make multiple hydrogen bonds with guanines and that Lys5 interacts with the phosphate backbone. The symmetry ofthe complex breaks down near the center of the site, and these results suggest a revision in the traditional alignment of the six λ operator sites.
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