7t2j

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of TEAD2 in a covalent complex with TED-642

Structural highlights

7t2j 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 2.7Å
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

Transcriptional enhanced associate domains (TEADs) are transcription factors that bind to cotranscriptional activators like the yes-associated protein (YAP) or its paralog transcriptional coactivator with a PDZ-binding motif (TAZ). TEAD.YAP/TAZ target genes are involved in tissue and immune homeostasis, organ size control, tumor growth, and metastasis. Here, we report isoindoline and octahydroisoindole small molecules with a cyanamide electrophile that forms a covalent bond with a conserved cysteine in the TEAD palmitate-binding cavity. Time- and concentration-dependent studies against TEAD1-4 yielded second-order rate constants k(inact)/K(I) greater than 100 M(-1) s(-1). Compounds inhibited YAP1 binding to TEADs with submicromolar IC(50) values. Cocrystal structures with TEAD2 enabled structure-activity relationship studies. In mammalian cells, compounds suppressed CTGF mRNA levels and inhibited TEAD1-4 transcriptional activity with submicromolar IC(50) values. Inhibition of TEAD binding to YAP1 in mammalian cells was also observed. Several compounds inhibited the cell viability of sarcoma, hepatocellular carcinoma, glioblastoma, and breast cancer cells with single-digit micromolar IC(50) values.

Small-Molecule Cyanamide Pan-TEAD.YAP1 Covalent Antagonists.,Bum-Erdene K, Yeh IJ, Gonzalez-Gutierrez G, Ghozayel MK, Pollok K, Meroueh SO J Med Chem. 2023 Jan 12;66(1):266-284. doi: 10.1021/acs.jmedchem.2c01189. Epub , 2022 Dec 23. PMID:36562717^[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
↑ Bum-Erdene K, Yeh IJ, Gonzalez-Gutierrez G, Ghozayel MK, Pollok K, Meroueh SO. Small-Molecule Cyanamide Pan-TEAD·YAP1 Covalent Antagonists. J Med Chem. 2023 Jan 12;66(1):266-284. PMID:36562717 doi:10.1021/acs.jmedchem.2c01189

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/7t2j"

Categories: Homo sapiens | Large Structures | Bum-Erdene K | Gonzalez-Gutierrez G | Meroueh SO

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[7t2j]] 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=7T2J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T2J 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]] 2.7&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E8Y:4-[3-(trifluoromethyl)anilino]-1,3-dihydro-2H-isoindole-2-carbonitrile'>E8Y</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E8Y:4-[[3-(trifluoromethyl)phenyl]amino]-1,3-dihydroisoindole-2-carbonitrile'>E8Y</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=7t2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t2j OCA], [https://pdbe.org/7t2j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t2j RCSB], [https://www.ebi.ac.uk/pdbsum/7t2j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t2j ProSAT]</span></td></tr>
 </table>

7t2j

From Proteopedia

Current revision

Crystal Structure of TEAD2 in a covalent complex with TED-642

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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