Molecular basis of sequence-specific single-stranded DNA recognition by KH domains: solution structure of a complex between hnRNP K KH3 and single-stranded DNA

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Abstract
To elucidate the basis of sequence‐specific single‐stranded (ss) DNA recognition by K homology (KH) domains, we have solved the solution structure of a complex between the KH3 domain of the transcriptional regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K) and a 10mer ssDNA. We show that hnRNP K KH3 specifically recognizes a tetrad of sequence 5′d‐TCCC. The complex is stabilized by a dense network of methyl‐oxygen hydrogen bonds involving the methyl groups of three isoleucine residues and the O2 and N3 atoms of the two central cytosine bases. Comparison with the recently solved structure of a specific protein–ssDNA complex involving the KH3 and KH4 domains of the far upstream element (FUSE) binding protein FBP suggests that the amino acid located five residues N‐terminal of the invariant GXXG motif, which is characteristic of all KH domains, plays a crucial role in discrimination of the first two bases of the tetrad.