8c04 - Revision history

OCA at 16:10, 14 March 2024

OCA — Thu, 14 Mar 2024 16:10:01 GMT

←Older revision		Revision as of 16:10, 14 March 2024
Line 10:		Line 10:
	== Function ==		== 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.		[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 ==
-	Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERalpha) protein. Two classes of fragments-a covalent and a noncovalent fragment-were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERalpha interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.
-
-	From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.,Visser EJ, Jaishankar P, Sijbesma E, Pennings MAM, Vandenboorn EMF, Guillory X, Neitz RJ, Morrow J, Dutta S, Renslo AR, Brunsveld L, Arkin MR, Ottmann C Angew Chem Int Ed Engl. 2023 Jul 16:e202308004. doi: 10.1002/anie.202308004. PMID:37455289<ref>PMID:37455289</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 8c04" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 10:36, 2 August 2023

OCA — Wed, 02 Aug 2023 10:36:14 GMT

←Older revision		Revision as of 10:36, 2 August 2023
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 8c04 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Co-soaked stabilizers for ERa - 14-3-3 interaction (884_AZ354)==
		+	<StructureSection load='8c04' size='340' side='right'caption='[[8c04]], [[Resolution\|resolution]] 1.10Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8c04]] 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=8C04 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8C04 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]] 1.1Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GEH:2-(4-chloranylphenoxy)-2-methyl-~{N}-(2-sulfanylethyl)propanamide'>GEH</scene>, <scene name='pdbligand=LF5:4-chloranyl-7-propan-2-yloxy-1-benzothiophene-2-carboximidamide'>LF5</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=8c04 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8c04 OCA], [https://pdbe.org/8c04 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8c04 RCSB], [https://www.ebi.ac.uk/pdbsum/8c04 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8c04 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 ==
		+	Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERalpha) protein. Two classes of fragments-a covalent and a noncovalent fragment-were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERalpha interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.

-	~~Authors:~~ Visser, E.J., ~~Sijbesma~~, E., ~~Ottmann~~, C.	+	From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking.,Visser EJ, Jaishankar P, Sijbesma E, Pennings MAM, Vandenboorn EMF, Guillory X, Neitz RJ, Morrow J, Dutta S, Renslo AR, Brunsveld L, Arkin MR, Ottmann C Angew Chem Int Ed Engl. 2023 Jul 16:e202308004. doi: 10.1002/anie.202308004. PMID:37455289<ref>PMID:37455289</ref>

-	~~Description: Co~~-~~soaked stabilizers for ERa~~ -~~14-3-3 interaction (884_AZ354)~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Sijbesma, E~~]]	+	<div class="pdbe-citations 8c04" style="background-color:#fffaf0;"></div>
-	[[Category: Ottmann, C]]	+	== References ==
-	[[Category: ~~Visser,~~ E.J]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Ottmann C]]
		+	[[Category: Sijbesma E]]
		+	[[Category: Visser EJ]]

OCA at 04:53, 18 January 2023

OCA — Wed, 18 Jan 2023 04:53:20 GMT

←Older revision		Revision as of 04:53, 18 January 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8c04 is ON HOLD	+	The entry 8c04 is ON HOLD until Paper Publication

	Authors: Visser, E.J., Sijbesma, E., Ottmann, C.		Authors: Visser, E.J., Sijbesma, E., Ottmann, C.

OCA at 05:31, 28 December 2022

OCA — Wed, 28 Dec 2022 05:31:55 GMT

←Older revision		Revision as of 05:31, 28 December 2022
Line 5:		Line 5:
	Authors: Visser, E.J., Sijbesma, E., Ottmann, C.		Authors: Visser, E.J., Sijbesma, E., Ottmann, C.

-	Description: co-soaked stabilizers for ERa -14-3-3 interaction (884_AZ354)	+	Description: Co-soaked stabilizers for ERa -14-3-3 interaction (884_AZ354)
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Sijbesma, E]]		[[Category: Sijbesma, E]]
	[[Category: Ottmann, C]]		[[Category: Ottmann, C]]
	[[Category: Visser, E.J]]		[[Category: Visser, E.J]]

OCA: Protected "8c04" [edit=sysop:move=sysop]

OCA — Wed, 21 Dec 2022 06:19:55 GMT

Protected "8c04" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:19, 21 December 2022

OCA: New page: '''Unreleased structure''' The entry 8c04 is ON HOLD Authors: Visser, E.J., Sijbesma, E., Ottmann, C. Description: co-soaked stabilizers for ERa -14-3-3 interaction (884_AZ354) [[Categ...

OCA — Wed, 21 Dec 2022 06:19:54 GMT

New page: '''Unreleased structure''' The entry 8c04 is ON HOLD Authors: Visser, E.J., Sijbesma, E., Ottmann, C. Description: co-soaked stabilizers for ERa -14-3-3 interaction (884_AZ354) [[Categ...

New page

'''Unreleased structure'''

The entry 8c04 is ON HOLD

Authors: Visser, E.J., Sijbesma, E., Ottmann, C.

Description: co-soaked stabilizers for ERa -14-3-3 interaction (884_AZ354)
[[Category: Unreleased Structures]]
[[Category: Sijbesma, E]]
[[Category: Ottmann, C]]
[[Category: Visser, E.J]]