National Institutes of Health

The solution structure of the specific complex be-tween the high mobility group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the human tes-tis-determining gene, and its DNA target site in the promoter of the M~illerian inhibitory substance gene has been determined by multidimensional NMR spec-troscopy, hSRY-HMG has a twisted L shape that pres-ents a concave surface (made up of three helices and the N- and C-terminal strands) to the DNA for se-quence-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 in the complex has an overall 70 °-80 ° bend and is helically unwound relative to classical A- and B-DNA. The structure of the complex reveals the origin of sequence-specific binding within the HMG-1/ HMG-2 family and provides a framework for under-standing the effects of point mutations that cause 46X,Y sex reversal at the atomic level