The structure of a chromosomal high mobility group protein-DNA complex reveals sequence-neutral mechanisms important for non-sequence-specific DNA recognition

The high mobility group (HMG) chromosomal proteins, which are common to all eukaryotes, bind DNA in a non-sequence-specific fashion to promote chromat in function and gene regulation. They interact directly with nucleosomes an d are believed to be modulators of chromatin structure. They are also impor tant in V(D)J recombination and in activating a number of regulators of gen e expression, including p53, Hox transcription factors and steroid hormone receptors, by increasing their affinity for DNA. The X-ray crystal structur e, at 2.2 Angstrom resolution, of the HMG domain of the Drosophila melanoga ster protein, HMG-D, bound to DNA provides the first detailed view of a chr omosomal HMG domain interacting with linear DNA and reveals the molecular b asis of non-sequence-specific DNA recognition. Ser10 forms water-mediated h ydrogen bonds to DNA bases, and Va132 with Thr33 partially intercalates the DNA, These two 'sequence-neutral' mechanisms of DNA binding substitute for base-specific hydrogen bonds made by equivalent residues of the sequence-s pecific HMG domain protein, lymphoid enhancer factor-1. The use of multiple intercalations and water-mediated DNA contacts may prove to be generally i mportant mechanisms by which chromosomal proteins bind to DNA in the minor groove.