OCA at 14:36, 20 September 2023

2023-09-20T14:36:36Z

←Older revision		Revision as of 14:36, 20 September 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8au2 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Small molecular stabilizer for ERalpha and 14-3-3 (1080293)==
		+	<StructureSection load='8au2' size='340' side='right'caption='[[8au2]], [[Resolution\|resolution]] 1.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8au2]] 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=8AU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8AU2 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]] 1.6Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=O3O:2-chloranyl-~{N}-[2-[1-[4-[(4-chlorophenyl)amino]piperidin-4-yl]carbonylpiperidin-4-yl]ethyl]ethanamide'>O3O</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=8au2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8au2 OCA], [https://pdbe.org/8au2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8au2 RCSB], [https://www.ebi.ac.uk/pdbsum/8au2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8au2 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/1433S_HUMAN 1433S_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity). p53-regulated inhibitor of G2/M progression.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3sigma bound to several of its clients, including ERalpha and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3sigma/ERalpha complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3sigma/C-RAF up to 150 muM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3sigma/ERalpha interface and locking the conformation with a spirocycle, the optimized covalent stabilizer 181 achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development.

-	~~Authors: Visser~~, ~~E.J~~., ~~Vandenboorn~~, E.M~~.F.~~, ~~Ottmann~~, C.	+	Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3sigma/ERalpha Protein-Protein Interaction from Nonselective Fragments.,Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR J Am Chem Soc. 2023 Sep 20;145(37):20328-20343. doi: 10.1021/jacs.3c05161. Epub , 2023 Sep 7. PMID:37676236<ref>PMID:37676236</ref>

-	~~Description: Small molecular stabilizer for ERalpha and 14~~-3-~~3 (1080293)~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Ottmann, C]]	+	<div class="pdbe-citations 8au2" style="background-color:#fffaf0;"></div>
-	[[Category: Vandenboorn~~, E.M.F~~]]	+	== References ==
-	[[Category: Visser~~, E.J~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Ottmann C]]
		+	[[Category: Vandenboorn EMF]]
		+	[[Category: Visser EJ]]

OCA at 04:31, 28 September 2022

2022-09-28T04:31:41Z

←Older revision		Revision as of 04:31, 28 September 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8au2 is ON HOLD	+	The entry 8au2 is ON HOLD until Paper Publication

	Authors: Visser, E.J., Vandenboorn, E.M.F., Ottmann, C.		Authors: Visser, E.J., Vandenboorn, E.M.F., Ottmann, C.

OCA: Protected "8au2" [edit=sysop:move=sysop]

2022-08-31T05:28:51Z

Protected "8au2" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:28, 31 August 2022

OCA: New page: '''Unreleased structure''' The entry 8au2 is ON HOLD Authors: Visser, E.J., Vandenboorn, E.M.F., Ottmann, C. Description: Small molecular stabilizer for ERalpha and 14-3-3 (1080293) [[...

2022-08-31T05:28:50Z

New page: '''Unreleased structure''' The entry 8au2 is ON HOLD Authors: Visser, E.J., Vandenboorn, E.M.F., Ottmann, C. Description: Small molecular stabilizer for ERalpha and 14-3-3 (1080293) [[...

New page

'''Unreleased structure'''

The entry 8au2 is ON HOLD

Authors: Visser, E.J., Vandenboorn, E.M.F., Ottmann, C.

Description: Small molecular stabilizer for ERalpha and 14-3-3 (1080293)
[[Category: Unreleased Structures]]
[[Category: Ottmann, C]]
[[Category: Vandenboorn, E.M.F]]
[[Category: Visser, E.J]]

8au2 - Revision history

OCA at 14:36, 20 September 2023

OCA at 04:31, 28 September 2022

OCA: Protected "8au2" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8au2 is ON HOLD Authors: Visser, E.J., Vandenboorn, E.M.F., Ottmann, C. Description: Small molecular stabilizer for ERalpha and 14-3-3 (1080293) [[...