5n5t

From Proteopedia

(Difference between revisions)

Revision as of 12:27, 15 November 2023

14-3-3 sigma in complex with TAZ pS89 peptide and fragment NV2

Structural highlights

5n5t is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

WWTR1_HUMAN Epithelioid hemangioendothelioma.

Function

WWTR1_HUMAN Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role 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 STK3/MST2 and STK4/MST1, 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. WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation. Regulates the nuclear accumulation of SMADS and has a key role in coupling them to the transcriptional machinery such as the mediator complex. Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Proteins typically interact with multiple binding partners, and often different parts of their surfaces are employed to establish these protein-protein interactions (PPIs). Members of the class of 14-3-3 adapter proteins bind to several hundred other proteins in the cell. Multiple small molecules for the modulation of 14-3-3 PPIs have been disclosed; however, they all target the conserved phosphopeptide binding channel, so that selectivity is difficult to achieve. Here we report on the discovery of two individual secondary binding sites that have been identified by combining nuclear magnetic resonance-based fragment screening and X-ray crystallography. The two pockets that these fragments occupy are part of at least three physiologically relevant and structurally characterized 14-3-3 PPI interfaces, including those with serotonin N-acetyltransferase and plant transcription factor FT. In addition, the high degree of conservation of the two sites implies their relevance for 14-3-3 PPIs. This first identification of secondary sites on 14-3-3 proteins bound by small molecule ligands might facilitate the development of new chemical tool compounds for more selective PPI modulation.

Identification of Two Secondary Ligand Binding Sites in 14-3-3 Proteins Using Fragment Screening.,Sijbesma E, Skora L, Leysen S, Brunsveld L, Koch U, Nussbaumer P, Jahnke W, Ottmann C Biochemistry. 2017 Aug 1;56(30):3972-3982. doi: 10.1021/acs.biochem.7b00153. Epub, 2017 Jul 21. PMID:28681606^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kanai F, Marignani PA, Sarbassova D, Yagi R, Hall RA, Donowitz M, Hisaminato A, Fujiwara T, Ito Y, Cantley LC, Yaffe MB. TAZ: a novel transcriptional co-activator regulated by interactions with 14-3-3 and PDZ domain proteins. EMBO J. 2000 Dec 15;19(24):6778-91. PMID:11118213 doi:http://dx.doi.org/10.1093/emboj/19.24.6778
↑ Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008 Apr;28(7):2426-36. doi: 10.1128/MCB.01874-07. Epub 2008 Jan, 28. PMID:18227151 doi:http://dx.doi.org/10.1128/MCB.01874-07
↑ Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, Yaffe MB, Zandstra PW, Wrana JL. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol. 2008 Jul;10(7):837-48. doi: 10.1038/ncb1748. Epub 2008 Jun 22. PMID:18568018 doi:http://dx.doi.org/10.1038/ncb1748
↑ Di Palma T, D'Andrea B, Liguori GL, Liguoro A, de Cristofaro T, Del Prete D, Pappalardo A, Mascia A, Zannini M. TAZ is a coactivator for Pax8 and TTF-1, two transcription factors involved in thyroid differentiation. Exp Cell Res. 2009 Jan 15;315(2):162-75. doi: 10.1016/j.yexcr.2008.10.016. Epub, 2008 Oct 28. PMID:19010321 doi:http://dx.doi.org/10.1016/j.yexcr.2008.10.016
↑ Sijbesma E, Skora L, Leysen S, Brunsveld L, Koch U, Nussbaumer P, Jahnke W, Ottmann C. Identification of Two Secondary Ligand Binding Sites in 14-3-3 Proteins Using Fragment Screening. Biochemistry. 2017 Aug 1;56(30):3972-3982. doi: 10.1021/acs.biochem.7b00153. Epub, 2017 Jul 21. PMID:28681606 doi:http://dx.doi.org/10.1021/acs.biochem.7b00153

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5n5t"

Categories: Homo sapiens | Large Structures | Leysen S | Ottmann C | Sijbesma E

@@ Line 3: / Line 3: @@
 <StructureSection load='5n5t' size='340' side='right'caption='[[5n5t]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5n5t]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N5T OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5N5T FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5n5t]] 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=5N5T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5N5T FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8OB:4-[3,5-bis(chloranyl)pyridin-2-yl]oxyphenol'>8OB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8OB:4-[3,5-bis(chloranyl)pyridin-2-yl]oxyphenol'>8OB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></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=5n5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n5t OCA], [http://pdbe.org/5n5t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5n5t RCSB], [http://www.ebi.ac.uk/pdbsum/5n5t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5n5t ProSAT]</span></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=5n5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n5t OCA], [https://pdbe.org/5n5t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5n5t RCSB], [https://www.ebi.ac.uk/pdbsum/5n5t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5n5t ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/WWTR1_HUMAN WWTR1_HUMAN] Epithelioid hemangioendothelioma.
 == Function ==
-[[http://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/WWTR1_HUMAN WWTR1_HUMAN] Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role 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 STK3/MST2 and STK4/MST1, 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. WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation. Regulates the nuclear accumulation of SMADS and has a key role in coupling them to the transcriptional machinery such as the mediator complex. Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition.<ref>PMID:11118213</ref> <ref>PMID:18227151</ref> <ref>PMID:18568018</ref> <ref>PMID:19010321</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Leysen, S]]
+[[Category: Leysen S]]
-[[Category: Ottmann, C]]
+[[Category: Ottmann C]]
-[[Category: Sijbesma, E]]
+[[Category: Sijbesma E]]
-[[Category: 14-3-3]]
-[[Category: Fbdd]]
-[[Category: Fragment]]
-[[Category: Protein binding]]
-[[Category: Taz]]

5n5t

From Proteopedia

Revision as of 12:27, 15 November 2023

14-3-3 sigma in complex with TAZ pS89 peptide and fragment NV2

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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