SUNY at Albany
June 19-23, 2001
Protein - DNA Minor Groove Recognition
The protein-DNA contacts in the minor groove are mostly "non-sequence specific," but nevertheless the overall recognition is quite selective. To explore this phenomenon, we analyzed the minor groove interactions observed in 144 cocrystal structures (see Figure). We found that the number of atom-atom contacts between protein and DNA depends on the DNA structural features, in particular on the deoxyribose conformation. The C3'-endo sugars are more accessible in the minor groove compared to C2'-endo sugars. There are multiple contacts to the sugar rings, by both hydrophilic and hydrophobic amino acids, e.g., Asn, Arg, Phe. Sugar ring oxygens O4' play an important role in such interactions, e.g. Arg often forms a bridge between O4' and the adjacent bases. Importantly, the sugar "contact profiles" are different for the purines and pyrimidines, as the latter have preponderance for the C2'-to-C3'-endo transition. That the sugar-phosphate backbone bears information on the type of the attached base (purine versus pyrimidine), and selective interactions of proteins with the C2'- and C3'-endo sugars, may be a basis for the degenerated recognition code (1).
The proteinÐDNA "contact profiles" for different families of proteins are different in terms of the amino acids involved in the recognition: a-helices interact with the base edges predominantly through Asn and Tyr, while b-sheets through Val and Phe. These "non-sequence specific" contacts in the minor groove crucially depend on the DNA conformation and, in turn, on the DNA sequence. For instance, the Arg-248 in the minor groove of the p53/DNA complex "intercalates" between the sugars from the opposite DNA strands, and requires a narrow minor groove (hence, this Arg is placed at AA:TT step). By contrast, in the dimeric PurR/DNA complex, the Leu-54 residues intercalate between the bases and bend the duplex into the major groove (accordingly, intercalation occurs in CG:CG step). Such contacts are apparently critical for the cooperative mutual fit between DNA and protein, and should be properly placed in the sequence. Multiple contacts in the minor groove can provide a fast "pre-recognition" of the cognate DNA sites, as well as secure a low affinity to non-cognate sequences.
Protein-DNA interactions in the minor groove ("contact profiles"). The contacts are enumerated for 20 amino acids, assuming that the atom-atom distances are less than 4.0 A.References and Footnotes
M.Ye. Tolstorukov, R.L. Jernigan, and V.B. Zhurkin
Laboratory of Experimental and Computational Biology, National Cancer Institute, NIH
Bethesda, MD 20892