6hkf: Difference between revisions

Latest revision as of 05:18, 21 November 2024

Ternary complex of Estrogen Receptor alpha peptide and 14-3-3 sigma C42 mutant bound to disulfide fragment PPI stabilizer 4

Structural highlights

6hkf 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 1.801Å
Ligands:	G8T, MG, TPO
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.

Publication Abstract from PubMed

Modulation of protein-protein interactions (PPIs) by small molecules has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon association of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3sigma and a peptide derived from Estrogen Receptor alpha (ERalpha), an important breast cancer target that is negatively regulated by 14-3-3sigma. We identify orthosteric stabilizers that increase 14-3-3/ERalpha affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ERalpha-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.

Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers.,Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565^[1]

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

References

↑ Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C. Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers. J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565 doi:https://dx.doi.org/10.1021/jacs.8b11658

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Sijbesma E, Hallenbeck KK, Leysen S, de Vink PJ, Skora L, Jahnke W, Brunsveld L, Arkin MR, Ottmann C. Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers. J Am Chem Soc. 2019 Feb 19. doi: 10.1021/jacs.8b11658. PMID:30707565 doi:https://dx.doi.org/10.1021/jacs.8b11658

[1]

@@ Line 1: / Line 1: @@
 ==Ternary complex of Estrogen Receptor alpha peptide and 14-3-3 sigma C42 mutant bound to disulfide fragment PPI stabilizer 4==
-<StructureSection load='6hkf' size='340' side='right'  caption='[[6hkf]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+<StructureSection load='6hkf' size='340' side='right'caption='[[6hkf]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6hkf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HKF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HKF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6hkf]] 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=6HKF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HKF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G8T:(1~{S})-2,2-diphenyl-1-(2-sulfanylethylamino)propan-1-ol'>G8T</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]] 1.801&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G8T:(1~{S})-2,2-diphenyl-1-(2-sulfanylethylamino)propan-1-ol'>G8T</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SFN, HME1 ([http://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=6hkf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hkf OCA], [https://pdbe.org/6hkf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hkf RCSB], [https://www.ebi.ac.uk/pdbsum/6hkf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hkf ProSAT]</span></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=6hkf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hkf OCA], [http://pdbe.org/6hkf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hkf RCSB], [http://www.ebi.ac.uk/pdbsum/6hkf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hkf ProSAT]</span></td></tr>
 </table>
 == 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. [[http://www.uniprot.org/uniprot/ESR1_HUMAN ESR1_HUMAN]] Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Isoform 3 can bind to ERE and inhibit isoform 1.<ref>PMID:7651415</ref> <ref>PMID:10970861</ref> <ref>PMID:9328340</ref> <ref>PMID:10681512</ref> <ref>PMID:10816575</ref> <ref>PMID:11477071</ref> <ref>PMID:11682626</ref> <ref>PMID:15078875</ref> <ref>PMID:16043358</ref> <ref>PMID:15891768</ref> <ref>PMID:16684779</ref> <ref>PMID:18247370</ref> <ref>PMID:17932106</ref> <ref>PMID:19350539</ref> <ref>PMID:20705611</ref> <ref>PMID:21937726</ref> <ref>PMID:21330404</ref> <ref>PMID:22083956</ref>
+[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 ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6hkf" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[14-3-3 protein 3D structures|14-3-3 protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Arkin, M R]]
+[[Category: Large Structures]]
-[[Category: Hallenbeck, K K]]
+[[Category: Arkin MR]]
-[[Category: Leysen, S]]
+[[Category: Hallenbeck KK]]
-[[Category: Ottmann, C]]
+[[Category: Leysen S]]
-[[Category: Sijbesma, E]]
+[[Category: Ottmann C]]
-[[Category: Fragment]]
+[[Category: Sijbesma E]]
-[[Category: Protein binding]]
-[[Category: Protein-protein interaction]]
-[[Category: Stabilizer]]
-[[Category: Tethering]]

6hkf: Difference between revisions

Latest revision as of 05:18, 21 November 2024

Ternary complex of Estrogen Receptor alpha peptide and 14-3-3 sigma C42 mutant bound to disulfide fragment PPI stabilizer 4

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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