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5xjd

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==TEAD in complex with fragment==
==TEAD in complex with fragment==
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<StructureSection load='5xjd' size='340' side='right' caption='[[5xjd]], [[Resolution|resolution]] 2.22&Aring;' scene=''>
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<StructureSection load='5xjd' size='340' side='right'caption='[[5xjd]], [[Resolution|resolution]] 2.22&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5xjd]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XJD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XJD FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5xjd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XJD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XJD FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=87L:(2S)-2-phenyl-2-pyrrol-1-yl-ethanoic+acid'>87L</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=87L:(2S)-2-phenyl-2-pyrrol-1-yl-ethanoic+acid'>87L</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tead4, Tcf13r1, Tef3, Tefr1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xjd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xjd OCA], [http://pdbe.org/5xjd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xjd RCSB], [http://www.ebi.ac.uk/pdbsum/5xjd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xjd ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xjd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xjd OCA], [http://pdbe.org/5xjd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xjd RCSB], [http://www.ebi.ac.uk/pdbsum/5xjd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xjd ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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The Hippo pathway is a tumor suppressor pathway that is implicated in the regulation of organ size. The pathway has three components: the upstream regulatory factors, the kinase core, and the downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor). Formation of YAP/TAZ-TEAD complexes leads to the transcription of growth-promoting genes. Herein, we report the crystal structure of TAZ-TEAD4 complex, which reveals two binding modes. The first is similar to the published YAP-TEAD structure. The second is a unique binding mode, whereby two molecules of TAZ bind to and bridge two molecules of TEAD4. We validated the latter using cross-linking and multi-angle light scattering. Using siRNA, we showed that TAZ knockdown leads to a decrease in TEAD4 dimerization. Lastly, results from luciferase assays, using YAP/TAZ transfected or knockdown cells, give support to the non-redundancy of YAP/TAZ co-activators in regulating gene expression in the Hippo pathway.
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The Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site.
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Crystal structure of TAZ-TEAD complex reveals a distinct interaction mode from that of YAP-TEAD complex.,Kaan HYK, Chan SW, Tan SKJ, Guo F, Lim CJ, Hong W, Song H Sci Rep. 2017 May 17;7(1):2035. doi: 10.1038/s41598-017-02219-9. PMID:28515457<ref>PMID:28515457</ref>
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Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches.,Kaan HYK, Sim AYL, Tan SKJ, Verma C, Song H PLoS One. 2017 Jun 1;12(6):e0178381. doi: 10.1371/journal.pone.0178381., eCollection 2017. PMID:28570566<ref>PMID:28570566</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Large Structures]]
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[[Category: Lk3 transgenic mice]]
[[Category: Kaan, H Y.K]]
[[Category: Kaan, H Y.K]]
[[Category: Sim, A Y.L]]
[[Category: Sim, A Y.L]]

Revision as of 09:02, 1 May 2019

TEAD in complex with fragment

PDB ID 5xjd

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