MOLECULAR-BASIS OF HUMAN 46X,Y SEX REVERSAL REVEALED FROM THE 3-DIMENSIONAL SOLUTION STRUCTURE OF THE HUMAN SRY-DNA COMPLEX

The solution structure of the specific complex between the high mobili ty group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the hu man testis-determining gene, and its DNA target site in the promoter o f the Mullerian inhibitory substance gene has been determined by multi dimensional NMR spectroscopy. hSRY-HMG has a twisted L shape that pres ents a concave surface (made up of three helices and the N- and C-term inal strands) to the DNA for sequence-specific recognition. Binding of hSRY-HMG to its specific target site occurs exclusively in the minor groove and induces a large conformational change in the DNA. The DNA i n the complex has an overall 70 degrees-80 degrees bend and is helical ly unwound relative to classical A- and B-DNA. The structure of the co mplex reveals the origin of sequence-specific binding within the HMG-1 /HMG-2 family and provides a framework for understanding the effects o f point mutations that cause 46X, Y sex reversal at the atomic level.