OCA at 07:07, 2 February 2022

2022-02-02T07:07:02Z

←Older revision		Revision as of 07:07, 2 February 2022
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	==Crystal structure of hTEAD2 in complex with a trisubstituted pyrazole inhibitor==		==Crystal structure of hTEAD2 in complex with a trisubstituted pyrazole inhibitor==
-	<StructureSection load='6s69' size='340' side='right'caption='[[6s69]]' scene=''>	+	<StructureSection load='6s69' size='340' side='right'caption='[[6s69]], [[Resolution\|resolution]] 2.15Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S69 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6S69 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6s69]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S69 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6S69 FirstGlance]. <br>
-	</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=6s69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s69 OCA], [~~http~~://pdbe.org/6s69 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6s69 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6s69 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6s69 ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KX5:3-[3-(3,4-dichlorophenyl)-4-(2-phenylethylcarbamoyl)pyrazol-1-yl]propanoic+acid'>KX5</scene>, <scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6s60\|6s60]]</div></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TEAD2, TEF4 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6s69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s69 OCA], [https://pdbe.org/6s69 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6s69 RCSB], [https://www.ebi.ac.uk/pdbsum/6s69 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6s69 ProSAT]</span></td></tr>
	</table>		</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 Hippo pathway is involved in organ size control and tissue homeostasis by regulating cell growth, proliferation and apoptosis. It controls the phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) in order to control their nuclear import and their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several cancers making YAP/TAZ-TEAD interaction a new emerging anti-cancer target. We report the synthesis of a set of trisubstituted pyrazoles which bind to hTEAD2 at the interface 2 revealing for the first time a cryptic pocket created by the movement of the phenol ring of Y382. Compound 6 disrupts YAP/TAZ-TEAD interaction in HEK293T cells and inhibits TEAD target genes and cell proliferation in MDA-MB-231 cells. Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model.
		+
		+	Discovery of a cryptic site at the interface 2 of TEAD - Towards a new family of YAP/TAZ-TEAD inhibitors.,Sturbaut M, Bailly F, Coevoet M, Sileo P, Pugniere M, Liberelle M, Magnez R, Thuru X, Chartier-Harlin MC, Melnyk P, Gelin M, Allemand F, Guichou JF, Cotelle P Eur J Med Chem. 2021 Dec 15;226:113835. doi: 10.1016/j.ejmech.2021.113835. Epub, 2021 Sep 6. PMID:34509860<ref>PMID:34509860</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6s69" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Allemand F]]	+	[[Category: Allemand, F]]
-	[[Category: Guichou JF]]	+	[[Category: Guichou, J F]]
-	[[Category: Sturbaut M]]	+	[[Category: Sturbaut, M]]
		+	[[Category: Inhibitor]]
		+	[[Category: Tead2]]
		+	[[Category: Transcription]]

OCA at 10:47, 22 July 2020

2020-07-22T10:47:57Z

←Older revision		Revision as of 10:47, 22 July 2020
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-	'''Unreleased structure'''

-	~~The entry~~ 6s69 ~~is ON HOLD~~	+	==Crystal structure of hTEAD2 in complex with a trisubstituted pyrazole inhibitor==
-		+	<StructureSection load='6s69' size='340' side='right'caption='[[6s69]]' scene=''>
-	~~Authors~~: ~~Sturbaut~~, M., ~~Allemand~~, F., ~~Guichou~~, J.F.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S69 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6S69 FirstGlance]. <br>
-	~~Description: Crystal structure of hTEAD2 in complex with a trisubstituted pyrazole inhibitor~~	+	</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=6s69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s69 OCA], [http://pdbe.org/6s69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s69 RCSB], [http://www.ebi.ac.uk/pdbsum/6s69 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s69 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Sturbaut, M~~]]	+	__TOC__
-	[[Category: Guichou~~, J.F~~]]	+	</StructureSection>
-	[[Category: ~~Allemand, F~~]]	+	[[Category: Large Structures]]
		+	[[Category: Allemand F]]
		+	[[Category: Guichou JF]]
		+	[[Category: Sturbaut M]]

OCA: Protected "6s69" [edit=sysop:move=sysop]

2019-07-10T04:27:32Z

Protected "6s69" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:27, 10 July 2019

OCA: New page: '''Unreleased structure''' The entry 6s69 is ON HOLD Authors: Sturbaut, M., Allemand, F., Guichou, J.F. Description: Crystal structure of hTEAD2 in complex with a trisubstituted pyrazo...

2019-07-10T04:27:31Z

New page: '''Unreleased structure''' The entry 6s69 is ON HOLD Authors: Sturbaut, M., Allemand, F., Guichou, J.F. Description: Crystal structure of hTEAD2 in complex with a trisubstituted pyrazo...

New page

'''Unreleased structure'''

The entry 6s69 is ON HOLD

Authors: Sturbaut, M., Allemand, F., Guichou, J.F.

Description: Crystal structure of hTEAD2 in complex with a trisubstituted pyrazole inhibitor
[[Category: Unreleased Structures]]
[[Category: Sturbaut, M]]
[[Category: Guichou, J.F]]
[[Category: Allemand, F]]

6s69 - Revision history

OCA at 07:07, 2 February 2022

OCA at 10:47, 22 July 2020

OCA: Protected "6s69" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6s69 is ON HOLD Authors: Sturbaut, M., Allemand, F., Guichou, J.F. Description: Crystal structure of hTEAD2 in complex with a trisubstituted pyrazo...