6FBY

Crystal structure of C-terminal modified Tau peptide-hybrid 4.2b with 14-3-3sigma

Summary for 6FBY

• Entry DOI: 10.2210/pdb6fby/pdb
• Related: 6FAU 6FAV 6FAW 6FBW
• Descriptor: 14-3-3 protein sigma, ACE-ARG-THR-PRO-SEP-LEU-PRO-GLY, THR-PRO-SEP-LEU-PRO-GLY, ... (7 entities in total)
• Functional Keywords: tau 14-3-3 alzheimer, structural protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 55235.89

Authors

Andrei, S.A.,Meijer, F.A.,Ottmann, C.,Milroy, L.G. (deposition date: 2017-12-20, release date: 2018-05-16, Last modification date: 2024-10-16)

Primary citation

Andrei, S.A.,Meijer, F.A.,Neves, J.F.,Brunsveld, L.,Landrieu, I.,Ottmann, C.,Milroy, L.G.
Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes.
ACS Chem Neurosci, 9:2639-2654, 2018

PubMed Abstract: Current molecular hypotheses have not yet delivered marketable treatments for Alzheimer's disease (AD), arguably due to a lack of understanding 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 structure-guided development of modified peptide inhibitors of 14-3-3/Tau. 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, and X-ray crystallography. 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 as measured by NMR spectroscopy. 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.

PubMed: 29722962
DOI: 10.1021/acschemneuro.8b00118

Experimental method

X-RAY DIFFRACTION (1.5 Å)