6uyc: Difference between revisions
New page: '''Unreleased structure''' The entry 6uyc is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Crystal structure of TEAD2 bound to Compound 2== | ||
<StructureSection load='6uyc' size='340' side='right'caption='[[6uyc]], [[Resolution|resolution]] 1.66Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6uyc]] is a 2 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=6UYC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UYC 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]] 1.658Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QLV:N-{5-[(E)-2-(4,4-difluorocyclohexyl)ethenyl]-6-methoxypyridin-3-yl}methanesulfonamide'>QLV</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=6uyc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uyc OCA], [https://pdbe.org/6uyc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uyc RCSB], [https://www.ebi.ac.uk/pdbsum/6uyc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uyc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TEAD2_HUMAN TEAD2_HUMAN] 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 to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3'). May be involved in the gene regulation of neural development. Binds to the M-CAT motif.<ref>PMID:18579750</ref> <ref>PMID:19324877</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate the expression of multiple genes involved in cellular proliferation and survival. Recent work identified TEAD S-palmitoylation as critical for protein stability and activity as the lipid tail extends into a hydrophobic core of the protein. Here, we report the identification and characterization of a potent small molecule that binds the TEAD lipid pocket (LP) and disrupts TEAD S-palmitoylation. Using a variety of biochemical, structural, and cellular methods, we uncover that TEAD S-palmitoylation functions as a TEAD homeostatic protein level checkpoint and that dysregulation of this lipidation affects TEAD transcriptional activity in a dominant-negative manner. Furthermore, we demonstrate that targeting the TEAD LP is a promising therapeutic strategy for modulating the Hippo pathway, showing tumor stasis in a mouse xenograft model. | |||
Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling.,Holden JK, Crawford JJ, Noland CL, Schmidt S, Zbieg JR, Lacap JA, Zang R, Miller GM, Zhang Y, Beroza P, Reja R, Lee W, Tom JYK, Fong R, Steffek M, Clausen S, Hagenbeek TJ, Hu T, Zhou Z, Shen HC, Cunningham CN Cell Rep. 2020 Jun 23;31(12):107809. doi: 10.1016/j.celrep.2020.107809. PMID:32579935<ref>PMID:32579935</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6uyc" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Crawford JJ]] | |||
[[Category: Cunningham CN]] | |||
[[Category: Holden JK]] | |||
[[Category: Noland CL]] | |||
[[Category: Zbieg JR]] | |||
Latest revision as of 11:00, 11 October 2023
Crystal structure of TEAD2 bound to Compound 2Crystal structure of TEAD2 bound to Compound 2
Structural highlights
FunctionTEAD2_HUMAN 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 to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3'). May be involved in the gene regulation of neural development. Binds to the M-CAT motif.[1] [2] Publication Abstract from PubMedThe transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for the downstream effectors of the Hippo pathway, YAP and TAZ, to upregulate the expression of multiple genes involved in cellular proliferation and survival. Recent work identified TEAD S-palmitoylation as critical for protein stability and activity as the lipid tail extends into a hydrophobic core of the protein. Here, we report the identification and characterization of a potent small molecule that binds the TEAD lipid pocket (LP) and disrupts TEAD S-palmitoylation. Using a variety of biochemical, structural, and cellular methods, we uncover that TEAD S-palmitoylation functions as a TEAD homeostatic protein level checkpoint and that dysregulation of this lipidation affects TEAD transcriptional activity in a dominant-negative manner. Furthermore, we demonstrate that targeting the TEAD LP is a promising therapeutic strategy for modulating the Hippo pathway, showing tumor stasis in a mouse xenograft model. Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling.,Holden JK, Crawford JJ, Noland CL, Schmidt S, Zbieg JR, Lacap JA, Zang R, Miller GM, Zhang Y, Beroza P, Reja R, Lee W, Tom JYK, Fong R, Steffek M, Clausen S, Hagenbeek TJ, Hu T, Zhou Z, Shen HC, Cunningham CN Cell Rep. 2020 Jun 23;31(12):107809. doi: 10.1016/j.celrep.2020.107809. PMID:32579935[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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