View source for 6edb


==Crystal structure of SRY.hcGAS-21bp dsDNA complex==
<StructureSection load='6edb' size='340' side='right'caption='[[6edb]], [[Resolution|resolution]] 3.21&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6edb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EDB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EDB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.209&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6edb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6edb OCA], [https://pdbe.org/6edb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6edb RCSB], [https://www.ebi.ac.uk/pdbsum/6edb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6edb ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SRY_HUMAN SRY_HUMAN] Defects in SRY are the cause of 46,XY sex reversal type 1 (SRXY1) [MIM:[https://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:[https://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> 
== Function ==
[https://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> [https://www.uniprot.org/uniprot/CGAS_HUMAN CGAS_HUMAN] Nucleotidyltransferase that catalyzes formation of cyclic GMP-AMP (cGAMP) from ATP and GTP and exhibits antiviral activity. Has antiviral activity by acting as a key cytosolic DNA sensor, the presence of DNA in the cytoplasm being a danger signal that triggers the immune responses. Binds cytosolic DNA directly, leading to activation and synthesis of cGAMP, a second messenger that binds to and activates TMEM173/STING, thereby triggering type-I interferon production.<ref>PMID:21478870</ref> <ref>PMID:23258413</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The cyclic GMP-AMP synthase (cGAS)-cGAMP-STING pathway plays a key role in innate immunity, with cGAS sensing both pathogenic and mislocalized DNA in the cytoplasm. Human cGAS (h-cGAS) constitutes an important drug target for control of antiinflammatory responses that can contribute to the onset of autoimmune diseases. Recent studies have established that the positively charged N-terminal segment of cGAS contributes to enhancement of cGAS enzymatic activity as a result of DNA-induced liquid-phase condensation. We have identified an additional cGAS(CD)-DNA interface (labeled site-C; CD, catalytic domain) in the crystal structure of a human SRY.cGAS(CD)-DNA complex, with mutations along this basic site-C cGAS interface disrupting liquid-phase condensation, as monitored by cGAMP formation, gel shift, spin-down, and turbidity assays, as well as time-lapse imaging of liquid droplet formation. We expand on an earlier ladder model of cGAS dimers bound to a pair of parallel-aligned DNAs to propose a multivalent interaction-mediated cluster model to account for DNA-mediated condensation involving both the N-terminal domain of cGAS and the site-C cGAS-DNA interface. We also report the crystal structure of the h-cGAS(CD)-DNA complex containing a triple mutant that disrupts the site-C interface, with this complex serving as a future platform for guiding cGAS inhibitor development at the DNA-bound h-cGAS level. Finally, we solved the structure of RU.521 bound in two alternate alignments to apo h-cGAS(CD), thereby occupying more of the catalytic pocket and providing insights into further optimization of active-site-binding inhibitors.

Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation.,Xie W, Lama L, Adura C, Tomita D, Glickman JF, Tuschl T, Patel DJ Proc Natl Acad Sci U S A. 2019 May 29. pii: 1905013116. doi:, 10.1073/pnas.1905013116. PMID:31142647<ref>PMID:31142647</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6edb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adura C]]
[[Category: Glickman JF]]
[[Category: Lama L]]
[[Category: Patel DJ]]
[[Category: Tuschl T]]
[[Category: Xie W]]