View source for 9ixs


==Crystal structure of TEAD3 YAP binding domain with compound 1==
<StructureSection load='9ixs' size='340' side='right'caption='[[9ixs]], [[Resolution|resolution]] 2.91&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ixs]] is a 3 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=9IXS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9IXS 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]] 2.91&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L3K:~{N}-[(1~{S})-1-phenylethyl]-5-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1~{H}-isoquinoline-2-carboxamide'>A1L3K</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=9ixs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ixs OCA], [https://pdbe.org/9ixs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ixs RCSB], [https://www.ebi.ac.uk/pdbsum/9ixs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ixs ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TEAD3_HUMAN TEAD3_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 multiple functional elements of the human chorionic somatomammotropin-B gene enhancer.<ref>PMID:18579750</ref> <ref>PMID:19324877</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Hippo signaling pathway is critical for regulating cell growth, tissue homeostasis, and organ size. Dysregulation of this pathway has been associated with a range of pathologies, especially cancer, through its modulation of downstream effectors-Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ). These proteins bind to transcriptional enhanced associate domain (TEAD) proteins and function as transcription factors in the nucleus, producing oncogenic target genes such as CTGF and CYR61. TEAD proteins require palmitoylation via a covalent bond with cysteine in the central pocket to bind YAP/TAZ. Therefore, competitive inhibition that prevents palmitoylation could serve as an effective anticancer strategy. In this study, we analyzed the crystal structures of the known inhibitor VT-105 bound to TEAD3 to identify new binding spots that were previously unexplored, with the aim of discovering more potent compounds using structure-based drug design. Consequently, we identified a novel hydrogen-bonding site and discovered C-2, which effectively binds to this site, as confirmed by X-ray crystallography. Furthermore, C-2 exhibited stable pharmacokinetic properties and demonstrated impressive efficacy in a mouse xenograft model.

Structure-based optimization of TEAD inhibitors: Exploring a novel subpocket near Glu347 for the treatment of NF2-mutant cancer.,Kim JK, Kim J, Kim H, Jin H, Yoo Y, Fei X, Maeng HJ, Seo SY, Han G, No KT Bioorg Chem. 2025 Mar 27;159:108425. doi: 10.1016/j.bioorg.2025.108425. PMID:40168885<ref>PMID:40168885</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ixs" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Yoo Y]]