1j46

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{{STRUCTURE_1j46| PDB=1j46 | SCENE= }}
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==3D Solution NMR Structure of the Wild Type HMG-BOX Domain of the Human Male Sex Determining Factor Sry Complexed to DNA==
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===3D Solution NMR Structure of the Wild Type HMG-BOX Domain of the Human Male Sex Determining Factor Sry Complexed to DNA===
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<StructureSection load='1j46' size='340' side='right' caption='[[1j46]], [[NMR_Ensembles_of_Models | 1 NMR models]]' scene=''>
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{{ABSTRACT_PUBMED_11563911}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1j46]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1J46 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1J46 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1j47|1j47]]</td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1j46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1j46 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1j46 RCSB], [http://www.ebi.ac.uk/pdbsum/1j46 PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/SRY_HUMAN SRY_HUMAN]] Defects in SRY are the cause of 46,XY sex reversal type 1 (SRXY1) [MIM:[http://omim.org/entry/400044 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.<ref>PMID:11563911</ref> <ref>PMID:2247149</ref> <ref>PMID:8353496</ref> <ref>PMID:1570829</ref> <ref>PMID:1415266</ref> <ref>PMID:1339396</ref> <ref>PMID:8447323</ref> <ref>PMID:1483689</ref> <ref>PMID:8105086</ref> <ref>PMID:8019555</ref> <ref>PMID:7985018</ref> <ref>PMID:7717397</ref> <ref>PMID:7776083</ref> [:]<ref>PMID:9678356</ref> <ref>PMID:9521592</ref> <ref>PMID:9450909</ref> <ref>PMID:10670762</ref> [:]<ref>PMID:10852465</ref> <ref>PMID:10843173</ref> <ref>PMID:10721678</ref> <ref>PMID:12107262</ref> <ref>PMID:12793612</ref> <ref>PMID:17063144</ref> 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:[http://omim.org/entry/400045 400045]]. A condition in which male gonads develop in a genetic female (female to male sex reversal).<ref>PMID:9652903</ref> <ref>PMID:10602113</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/SRY_HUMAN 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'.<ref>PMID:11818535</ref> <ref>PMID:15170344</ref> <ref>PMID:16762365</ref> <ref>PMID:11563911</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/j4/1j46_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Disease==
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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<ref>PMID:11563911</ref>
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[[http://www.uniprot.org/uniprot/SRY_HUMAN SRY_HUMAN]] Defects in SRY are the cause of 46,XY sex reversal type 1 (SRXY1) [MIM:[http://omim.org/entry/400044 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.<ref>PMID:11563911</ref><ref>PMID:2247149</ref><ref>PMID:8353496</ref><ref>PMID:1570829</ref><ref>PMID:1415266</ref><ref>PMID:1339396</ref><ref>PMID:8447323</ref><ref>PMID:1483689</ref><ref>PMID:8105086</ref><ref>PMID:8019555</ref><ref>PMID:7985018</ref><ref>PMID:7717397</ref><ref>PMID:7776083</ref>[:]<ref>PMID:9678356</ref><ref>PMID:9521592</ref><ref>PMID:9450909</ref><ref>PMID:10670762</ref>[:]<ref>PMID:10852465</ref><ref>PMID:10843173</ref><ref>PMID:10721678</ref><ref>PMID:12107262</ref><ref>PMID:12793612</ref><ref>PMID:17063144</ref> 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:[http://omim.org/entry/400045 400045]]. A condition in which male gonads develop in a genetic female (female to male sex reversal).<ref>PMID:9652903</ref><ref>PMID:10602113</ref>
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/SRY_HUMAN 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'.<ref>PMID:11818535</ref><ref>PMID:15170344</ref><ref>PMID:16762365</ref><ref>PMID:11563911</ref>
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</div>
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== References ==
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==About this Structure==
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<references/>
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[[1j46]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1J46 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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<ref group="xtra">PMID:011563911</ref><references group="xtra"/><references/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Clore, G M.]]
[[Category: Clore, G M.]]

Revision as of 15:19, 29 September 2014

3D Solution NMR Structure of the Wild Type HMG-BOX Domain of the Human Male Sex Determining Factor Sry Complexed to DNA

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