6e5g
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human TEAD2-Yap binding domain covalently bound to an allosteric regulator== | |
| + | <StructureSection load='6e5g' size='340' side='right' caption='[[6e5g]], [[Resolution|resolution]] 2.43Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6e5g]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E5G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E5G FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HUY:1-(2-{[3-(trifluoromethyl)phenyl]amino}phenyl)ethan-1-one'>HUY</scene></td></tr> | ||
| + | <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=6e5g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e5g OCA], [http://pdbe.org/6e5g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e5g RCSB], [http://www.ebi.ac.uk/pdbsum/6e5g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e5g 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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The Hippo pathway coordinates extracellular signals onto the control of tissue homeostasis and organ size. Hippo signaling primarily regulates the ability of Yap1 to bind and co-activate TEA domain (TEAD) transcription factors. Yap1 tightly binds to TEAD4 via a large flat interface, making the development of small-molecule orthosteric inhibitors highly challenging. Here, we report small-molecule TEADYap inhibitors that rapidly and selectively form a covalent bond with a conserved cysteine located within the unique deep hydrophobic palmitate-binding pocket of TEADs. Inhibition of TEAD4 binding to Yap1 by these compounds was irreversible and occurred on a longer time scale. In mammalian cells, the compounds formed a covalent complex with TEAD4, inhibited its binding to Yap1, blocked its transcriptional activity, and suppressed expression of connective tissue growth factor. The compounds inhibited cell viability of patient-derived glioblastoma spheroids, making them suitable as chemical probes to explore Hippo signaling in cancer. | ||
| - | + | Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEADYap Protein-Protein Interaction.,Bum-Erdene K, Zhou D, Gonzalez-Gutierrez G, Ghozayel MK, Si Y, Xu D, Shannon HE, Bailey BJ, Corson TW, Pollok KE, Wells CD, Meroueh SO Cell Chem Biol. 2018 Dec 18. pii: S2451-9456(18)30432-X. doi:, 10.1016/j.chembiol.2018.11.010. PMID:30581134<ref>PMID:30581134</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 6e5g" style="background-color:#fffaf0;"></div> | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Bum-Erdene, K]] | [[Category: Bum-Erdene, K]] | ||
[[Category: Gonzalez-Gutierrez, G]] | [[Category: Gonzalez-Gutierrez, G]] | ||
| + | [[Category: Meroueh, S O]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Transcription-inhibitor complex]] | ||
Revision as of 06:35, 9 January 2019
Crystal structure of human TEAD2-Yap binding domain covalently bound to an allosteric regulator
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