6fby: Difference between revisions
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==Crystal structure of C-terminal modified Tau peptide-hybrid 4.2b with 14-3-3sigma== | ==Crystal structure of C-terminal modified Tau peptide-hybrid 4.2b with 14-3-3sigma== | ||
<StructureSection load='6fby' size='340' side='right' caption='[[6fby]], [[Resolution|resolution]] 1.50Å' scene=''> | <StructureSection load='6fby' size='340' side='right'caption='[[6fby]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6fby]] is a 4 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6fby]] is a 4 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=6FBY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FBY FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=D4H:(2~{R})-2-[(~{S})-(3-methylphenyl)-phenyl-methyl]pyrrolidine'>D4H</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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'>[https://proteopedia.org/fgij/fg.htm?mol=6fby FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fby OCA], [https://pdbe.org/6fby PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fby RCSB], [https://www.ebi.ac.uk/pdbsum/6fby PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fby ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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==See Also== | ==See Also== | ||
*[[Tau protein|Tau protein]] | *[[Tau protein 3D structures|Tau protein 3D structures]] | ||
*[[14-3-3 protein 3D structures|14-3-3 protein 3D structures]] | *[[14-3-3 protein 3D structures|14-3-3 protein 3D structures]] | ||
== References == | == References == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Andrei SA]] | ||
[[Category: | [[Category: Meijer FA]] | ||
[[Category: | [[Category: Milroy LG]] | ||
[[Category: | [[Category: Ottmann C]] | ||
Latest revision as of 10:57, 17 October 2024
Crystal structure of C-terminal modified Tau peptide-hybrid 4.2b with 14-3-3sigmaCrystal structure of C-terminal modified Tau peptide-hybrid 4.2b with 14-3-3sigma
Structural highlights
Publication Abstract from PubMedCurrent molecular hypotheses have yet to deliver marketable treatments for Alzheimer's disease (AD), arguably due to a lack of basic knowledge of AD biology, and an overreliance on conventional drug modalities. Protein-protein interactions (PPIs) are emerging drug targets, which show promise for the treatment of e.g. cancer, but are still underexploited for treating neurodegenerative diseases. 14-3-3 binding to phosphorylated Tau is a promising PPI drug target based on its reported destabilizing effect on microtubules, leading to enhanced neurofibrillary tangle formation as a potential cause of AD-related neurodegeneration. Inhibition of 14-3-3/Tau may therefore be neuroprotective. Previously, we reported the development of modified peptide inhibitors of 14-3-3/Tau using a novel structure-guided approach. Here, we report further efforts to optimize the binding mode and activity of our modified Tau peptides through a combination of chemical synthesis, biochemical assays, X-ray crystallography and NMR spectroscopy studies. Most notably, we were able to characterize two different high-affinity binding modes, both of which inhibited 14-3-3-binding to full-length PKA-phosphorylated Tau protein in vitro. Our findings, besides producing useful tool inhibitor compounds for studying 14-3-3/Tau, have enhanced our understanding of the molecular parameters for inhibiting 14-3-3/Tau, which are important milestones toward the establishment of our 14-3-3 PPI hypothesis. Inhibition of 14-3-3/Tau by hybrid small-molecule-peptides operating via two different binding modes.,Andrei SA, Meijer F, Neves J, Brunsveld L, Landrieu I, Ottmann C, Milroy LG ACS Chem Neurosci. 2018 May 3. doi: 10.1021/acschemneuro.8b00118. PMID:29722962[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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