6fby

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 6fby is a 4 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 1.5Å Ligands: , , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Current 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tau protein 3D structures 14-3-3 protein 3D structures

spinqualitylabelsall models 6fby, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image