View source for 5odg


==Crystal structure of Smad3-MH1 bound to the GGCT site.==
<StructureSection load='5odg' size='340' side='right'caption='[[5odg]], [[Resolution|resolution]] 2.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5odg]] 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=5ODG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ODG 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]] 2.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <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=5odg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5odg OCA], [https://pdbe.org/5odg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5odg RCSB], [https://www.ebi.ac.uk/pdbsum/5odg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5odg ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN] Defects in SMAD3 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].  Defects in SMAD3 are the cause of Loeys-Dietz syndrome 3 (LDS3) [MIM:[https://omim.org/entry/613795 613795]. An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. Note=SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.<ref>PMID:21778426</ref> <ref>PMID:21217753</ref> 
== Function ==
[https://www.uniprot.org/uniprot/SMAD3_HUMAN SMAD3_HUMAN] Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures (By similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.<ref>PMID:9732876</ref> <ref>PMID:9892009</ref> <ref>PMID:10995748</ref> <ref>PMID:15241418</ref> <ref>PMID:15588252</ref> <ref>PMID:16156666</ref> <ref>PMID:16751101</ref> <ref>PMID:17327236</ref> <ref>PMID:16862174</ref> <ref>PMID:19289081</ref> <ref>PMID:19218245</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Smad transcription factors activated by TGF-beta or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene. The structures revealed a 5-bp consensus sequence GGC(GC)|(CG) as the binding site for both TGF-beta and BMP-activated Smads and for Smad4. These 5GC motifs are highly represented as clusters in Smad-bound regions genome-wide. Our results provide a basis for understanding the functional adaptability of Smads in different cellular contexts, and their dependence on lineage-determining transcription factors to target specific genes in TGF-beta and BMP pathways.

Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors.,Martin-Malpartida P, Batet M, Kaczmarska Z, Freier R, Gomes T, Aragon E, Zou Y, Wang Q, Xi Q, Ruiz L, Vea A, Marquez JA, Massague J, Macias MJ Nat Commun. 2017 Dec 12;8(1):2070. doi: 10.1038/s41467-017-02054-6. PMID:29234012<ref>PMID:29234012</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5odg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kaczmarska Z]]
[[Category: Macias MJ]]
[[Category: Marquez JA]]