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6uyc

From Proteopedia

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Crystal structure of TEAD2 bound to Compound 2

Structural highlights

6uyc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.658Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC, Guan KL. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008 Jul 15;22(14):1962-71. Epub 2008 Jun 25. PMID:18579750 doi:10.1101/gad.1664408
↑ Zhang H, Liu CY, Zha ZY, Zhao B, Yao J, Zhao S, Xiong Y, Lei QY, Guan KL. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition. J Biol Chem. 2009 May 15;284(20):13355-62. doi: 10.1074/jbc.M900843200. Epub 2009, Mar 26. PMID:19324877 doi:10.1074/jbc.M900843200
↑ 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. Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of Hippo Pathway Signaling. Cell Rep. 2020 Jun 23;31(12):107809. doi: 10.1016/j.celrep.2020.107809. PMID:32579935 doi:http://dx.doi.org/10.1016/j.celrep.2020.107809

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6uyc"

@@ Line 3: / Line 3: @@
 <StructureSection load='6uyc' size='340' side='right'caption='[[6uyc]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6uyc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://proteopedia.org/fgij/fg.htm?mol=6UYC FirstGlance]. <br>
+<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='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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.658&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TEAD2, TEF4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://proteopedia.org/fgij/fg.htm?mol=6uyc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uyc OCA], [http://pdbe.org/6uyc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uyc RCSB], [http://www.ebi.ac.uk/pdbsum/6uyc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uyc ProSAT]</span></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 ==
-[[http://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>
+[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 ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Crawford, J J]]
+[[Category: Crawford JJ]]
-[[Category: Cunningham, C N]]
+[[Category: Cunningham CN]]
-[[Category: Holden, J K]]
+[[Category: Holden JK]]
-[[Category: Noland, C L]]
+[[Category: Noland CL]]
-[[Category: Zbieg, J R]]
+[[Category: Zbieg JR]]
-[[Category: Palmitoylation inhibitor]]
-[[Category: Tead]]
-[[Category: Transcription inhibitor]]
-[[Category: Transcription-inhibitor complex]]
-[[Category: Yap binding domain]]

6uyc

From Proteopedia

Current revision

Crystal structure of TEAD2 bound to Compound 2

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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