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 [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. 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 [https://proteopedia.org/fgij/fg.htm?mol=5XJD FirstGlance]. <br>
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</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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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.22&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=87L:(2S)-2-phenyl-2-pyrrol-1-yl-ethanoic+acid'>87L</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5xjd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xjd OCA], [https://pdbe.org/5xjd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xjd RCSB], [https://www.ebi.ac.uk/pdbsum/5xjd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xjd ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/TEAD4_MOUSE TEAD4_MOUSE]] Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif (By similarity). Might play a role in the embryonic development of skeletal muscle.
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[https://www.uniprot.org/uniprot/TEAD4_MOUSE TEAD4_MOUSE] Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif (By similarity). Might play a role in the embryonic development of skeletal muscle.
<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: Kaan, H Y.K]]
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[[Category: Large Structures]]
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[[Category: Sim, A Y.L]]
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[[Category: Mus musculus]]
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[[Category: Song, H]]
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[[Category: Kaan HYK]]
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[[Category: Tan, S K.J]]
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[[Category: Sim AYL]]
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[[Category: Verma, C]]
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[[Category: Song H]]
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[[Category: Transcription]]
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[[Category: Tan SKJ]]
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[[Category: Transcription factor]]
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[[Category: Verma C]]

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TEAD in complex with fragment

PDB ID 5xjd

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