1j46 is a 3 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
[SRY_HUMAN] Defects in SRY are the cause of 46,XY sex reversal type 1 (SRXY1) [MIM:400044]. A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. Patients manifest rapid and early degeneration of their gonads, which are present in the adult as 'streak gonads', consisting mainly of fibrous tissue and variable amounts of ovarian stroma. As a result these patients do not develop secondary sexual characteristics at puberty. The external genitalia in these subjects are completely female, and Muellerian structures are normal.[1][2][3][4][5][6][7][8][9][10][11][12][13] [:][14][15][16][17] [:][18][19][20][21][22][23] Note=A 45,X chromosomal aberration involving SRY is found in Turner syndrome, a disease characterized by gonadal dysgenesis with short stature, "streak gonads", variable abnormalities such as webbing of the neck, cubitus valgus, cardiac defects, low posterior hair line. The phenotype is female. Defects in SRY are the cause of 46,XX sex reversal type 1 (SRXX1) [MIM:400045]. A condition in which male gonads develop in a genetic female (female to male sex reversal).[24][25]
Function
[SRY_HUMAN] Transcriptional regulator that controls a genetic switch in male development. It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells (By similarity). In male adult brain involved in the maintenance of motor functions of dopaminergic neurons (By similarity). Involved in different aspects of gene regulation including promoter activation or repression (By similarity). Promotes DNA bending. SRY HMG box recognizes DNA by partial intercalation in the minor groove. Also involved in pre-mRNA splicing. Binds to the DNA consensus sequence 5'-[AT]AACAA[AT]-3'.[26][27][28][29]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The HMG-box domain of the human male sex-determining factor SRY, hSRY(HMG) (comprising residues 57-140 of the full-length sequence), binds DNA sequence-specifically in the minor groove, resulting in substantial DNA bending. The majority of point mutations resulting in 46X,Y sex reversal are located within this domain. One clinical de novo mutation, M64I in the full-length hSRY sequence, which corresponds to M9I in the present hSRY(HMG) construct, acts principally by reducing the extent of DNA bending. To elucidate the structural consequences of the M9I mutation, we have solved the 3D solution structures of wild-type and M9I hSRY(HMG) complexed to a DNA 14mer by NMR, including the use of residual dipolar couplings to derive long-range orientational information. We show that the average bend angle (derived from an ensemble of 400 simulated annealing structures for each complex) is reduced by approximately 13 degrees from 54(+/-2) degrees in the wild-type complex to 41(+/-2) degrees in the M9I complex. The difference in DNA bending can be localized directly to changes in roll and tilt angles in the ApA base-pair step involved in interactions with residue 9 and partial intercalation of Ile13. The larger bend angle in the wild-type complex arises as a direct consequence of steric repulsion of the sugar of the second adenine by the bulky S(delta) atom of Met9, whose position is fixed by a hydrogen bond with the guanidino group of Arg17. In the M9I mutant, this hydrogen bond can no longer occur, and the less bulky C(gamma)m methyl group of Ile9 braces the sugar moieties of the two adenine residues, thereby decreasing the roll and tilt angles at the ApA step by approximately 8 degrees and approximately 5 degrees, respectively, and resulting in an overall difference in bend angle of approximately 13 degrees between the two complexes. To our knowledge, this is one of the first examples where the effects of a clinical mutation involving a protein-DNA complex have been visualized at the atomic level.
Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation.,Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911[30]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911 doi:https://dx.doi.org/10.1006/jmbi.2001.4977
↑Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990 Nov 29;348(6300):448-50. PMID:2247149 doi:https://dx.doi.org/10.1038/348448A0
↑Affara NA, Chalmers IJ, Ferguson-Smith MA. Analysis of the SRY gene in 22 sex-reversed XY females identifies four new point mutations in the conserved DNA binding domain. Hum Mol Genet. 1993 Jun;2(6):785-9. PMID:8353496
↑Vilain E, McElreavey K, Jaubert F, Raymond JP, Richaud F, Fellous M. Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. Am J Hum Genet. 1992 May;50(5):1008-11. PMID:1570829
↑Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz GD. Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet. 1992 Nov;51(5):979-84. PMID:1415266
↑Hawkins JR, Taylor A, Berta P, Levilliers J, Van der Auwera B, Goodfellow PN. Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet. 1992 Feb;88(4):471-4. PMID:1339396
↑Braun A, Kammerer S, Cleve H, Lohrs U, Schwarz HP, Kuhnle U. True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case. Am J Hum Genet. 1993 Mar;52(3):578-85. PMID:8447323
↑Jager RJ, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G. A familial mutation in the testis-determining gene SRY shared by both sexes. Hum Genet. 1992 Dec;90(4):350-5. PMID:1483689
↑Zeng YT, Ren ZR, Zhang ML, Huang Y, Zeng FY, Huang SZ. A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis. J Med Genet. 1993 Aug;30(8):655-7. PMID:8105086
↑Poulat F, Soullier S, Goze C, Heitz F, Calas B, Berta P. Description and functional implications of a novel mutation in the sex-determining gene SRY. Hum Mutat. 1994;3(3):200-4. PMID:8019555 doi:https://dx.doi.org/10.1002/humu.1380030305
↑Haqq CM, King CY, Ukiyama E, Falsafi S, Haqq TN, Donahoe PK, Weiss MA. Molecular basis of mammalian sexual determination: activation of Mullerian inhibiting substance gene expression by SRY. Science. 1994 Dec 2;266(5190):1494-500. PMID:7985018
↑Schmitt-Ney M, Thiele H, Kaltwasser P, Bardoni B, Cisternino M, Scherer G. Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Am J Hum Genet. 1995 Apr;56(4):862-9. PMID:7717397
↑Hiort O, Gramss B, Klauber GT. True hermaphroditism with 46,XY karyotype and a point mutation in the SRY gene. J Pediatr. 1995 Jun;126(6):1022. PMID:7776083
↑Scherer G, Held M, Erdel M, Meschede D, Horst J, Lesniewicz R, Midro AT. Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY gonadal dysgenesis cases without SRY mutations. Cytogenet Cell Genet. 1998;80(1-4):188-92. PMID:9678356
↑Domenice S, Yumie Nishi M, Correia Billerbeck AE, Latronico AC, Aparecida Medeiros M, Russell AJ, Vass K, Marino Carvalho F, Costa Frade EM, Prado Arnhold IJ, Bilharinho Mendonca B. A novel missense mutation (S18N) in the 5' non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Hum Genet. 1998 Feb;102(2):213-5. PMID:9521592
↑Imai A, Takagi A, Tamaya T. A novel sex-determining region on Y (SRY) missense mutation identified in a 46,XY female and also in the father. Endocr J. 1999 Oct;46(5):735-9. PMID:10670762
↑Schaffler A, Barth N, Winkler K, Zietz B, Rummele P, Knuchel R, Scholmerich J, Palitzsch KD. Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor. J Clin Endocrinol Metab. 2000 Jun;85(6):2287-92. PMID:10852465
↑Canto P, de la Chesnaye E, Lopez M, Cervantes A, Chavez B, Vilchis F, Reyes E, Ulloa-Aguirre A, Kofman-Alfaro S, Mendez JP. A mutation in the 5' non-high mobility group box region of the SRY gene in patients with Turner syndrome and Y mosaicism. J Clin Endocrinol Metab. 2000 May;85(5):1908-11. PMID:10843173
↑Okuhara K, Tajima T, Nakae J, Fujieda K. A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal. J Hum Genet. 2000;45(2):112-4. PMID:10721678 doi:10.1007/s100380050026
↑Jordan BK, Jain M, Natarajan S, Frasier SD, Vilain E. Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. J Clin Endocrinol Metab. 2002 Jul;87(7):3428-32. PMID:12107262
↑Maier EM, Leitner C, Lohrs U, Kuhnle U. True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene. J Pediatr Endocrinol Metab. 2003 Apr-May;16(4):575-80. PMID:12793612
↑Gimelli G, Gimelli S, Dimasi N, Bocciardi R, Di Battista E, Pramparo T, Zuffardi O. Identification and molecular modelling of a novel familial mutation in the SRY gene implicated in the pure gonadal dysgenesis. Eur J Hum Genet. 2007 Jan;15(1):76-80. Epub 2006 Oct 25. PMID:17063144 doi:10.1038/sj.ejhg.5201719
↑Inoue H, Nomura M, Yanase T, Ichino I, Goto K, Ikuyama S, Takayanagi R, Nawata H. A rare case of 46,XX true hermaphroditism with hidden mosaicism with sex-determining region Y chromosome-bearing cells in the gonads. Intern Med. 1998 May;37(5):467-71. PMID:9652903
↑Margarit E, Coll MD, Oliva R, Gomez D, Soler A, Ballesta F. SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite. Am J Med Genet. 2000 Jan 3;90(1):25-8. PMID:10602113
↑Ohe K, Lalli E, Sassone-Corsi P. A direct role of SRY and SOX proteins in pre-mRNA splicing. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1146-51. Epub 2002 Jan 29. PMID:11818535 doi:10.1073/pnas.022645899
↑Phillips NB, Nikolskaya T, Jancso-Radek A, Ittah V, Jiang F, Singh R, Haas E, Weiss MA. Sry-directed sex reversal in transgenic mice is robust with respect to enhanced DNA bending: comparison of human and murine HMG boxes. Biochemistry. 2004 Jun 8;43(22):7066-81. PMID:15170344 doi:10.1021/bi049920a
↑Li B, Phillips NB, Jancso-Radek A, Ittah V, Singh R, Jones DN, Haas E, Weiss MA. SRY-directed DNA bending and human sex reversal: reassessment of a clinical mutation uncovers a global coupling between the HMG box and its tail. J Mol Biol. 2006 Jul 7;360(2):310-28. Epub 2006 May 9. PMID:16762365 doi:S0022-2836(06)00522-5
↑Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911 doi:https://dx.doi.org/10.1006/jmbi.2001.4977
↑Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911 doi:https://dx.doi.org/10.1006/jmbi.2001.4977
