Molecular basis of human 46X,Y sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex.
The solution structure of the specific complex between the high mobility group (HMG) domain of SRY (hSRY-HMG), the protein encoded by the human testis-determining gene, and its DNA target site in the promoter of the müllerian inhibitory substance gene has been determined by multidimensional NMR spectroscopy. hSRY-HMG has a twisted L shape that presents a concave surface (made up of three helices and the N- and C-terminal 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 in the complex has an overall 70 degrees-80 degrees 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 understanding the effects of point mutations that cause 46X,Y sex reversal at the atomic level.
Werner
M H
MH
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA.
Huth
J R
JR
Gronenborn
A M
AM
Clore
G M
GM
D054304:Anti-Mullerian Hormone; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D012734:Disorders of Sex Development; D005260:Female; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000235:genetics*; D006801:Humans; D007621:Karyotyping; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D009687:Nuclear Proteins; D009841:Oligonucleotides / Q000737:chemistry; D017354:Point Mutation; D011485:Protein Binding; D012729:Sex Chromosome Aberrations / Q000235:genetics*; D012733:Sex Differentiation; D051876:Sex-Determining Region Y Protein; D013735:Testicular Hormones / Q000235:genetics*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014960:X Chromosome; D014998:Y Chromosome
D004268:DNA-Binding Proteins; D006023:Glycoproteins; D006131:Growth Inhibitors; D009687:Nuclear Proteins; D009841:Oligonucleotides; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D013735:Testicular Hormones; D014157:Transcription Factors; D054304:Anti-Mullerian Hormone