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 spe...

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Bibliographic Details
Published in:Cell 1995-06, Vol.81 (5), p.705-714
Main Authors: Werner, Milton H, Huth, Jeffrey R, Gronenborn, Angela M, Marius Clore, G
Format: Article
Language:English
Subjects:
Anti-Mullerian Hormone
Binding Sites
Disorders of Sex Development
DNA
DNA-Binding Proteins - chemistry
DNA-Binding Proteins - genetics
Female
Glycoproteins
Growth Inhibitors - genetics
high mobility group protein 1
high mobility group protein 2
Humans
Karyotyping
Magnetic Resonance Spectroscopy
Male
man
Models, Molecular
Nuclear Proteins
Oligonucleotides - chemistry
Point Mutation
Protein Binding
Sex Chromosome Aberrations - genetics
sex determination
Sex Differentiation
sex reversal
Sex-Determining Region Y Protein
SRY protein
Testicular Hormones - genetics
Transcription Factors
Transcription, Genetic
X Chromosome
Y Chromosome
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Summary: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°–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 understanding the effects of point mutations that cause 46X,Y sex reversal at the atomic level.
ISSN:0092-8674
1097-4172
DOI:10.1016/0092-8674(95)90532-4