PDBsum entry 6fbw

Structural protein

PDB id: 6fbw

Contents

Protein chains

227 a.a.

Ligands

ARG-THR-PRO-SEP-LEU-PRO-GLY

THR-PRO-SEP-LEU-PRO-GLY

D4K ×2

Metals

_NA ×4

_CL ×2

Waters ×670

PDB id:

6fbw

Name:

Structural protein

Title:

Crystal structure of c-terminal modified tau peptide-hybrid 4.2f-ii with 14-3-3sigma

Structure:

14-3-3 protein sigma. Chain: a, c. Synonym: epithelial cell marker protein 1,stratifin. Engineered: yes. Arg-thr-pro-sep-leu-pro-gly. Chain: b, d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: sfn, hme1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.45Å R-factor: 0.153 R-free: 0.178

Authors:

S.A.Andrei,F.A.Meijer,C.Ottmann,L.G.Milroy

Key ref:

S.A.Andrei et al. (2018). Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes. ACS Chem Neurosci, 9, 2639-2654. PubMed id: 29722962 DOI: 10.1021/acschemneuro.8b00118

Date:

20-Dec-17 Release date: 16-May-18

Protein chains

P31947  (1433S_HUMAN) -  14-3-3 protein sigma from Homo sapiens

Seq: 248 a.a.

Struc: 227 a.a.

DOI no: 10.1021/acschemneuro.8b00118

ACS Chem Neurosci 9:2639-2654 (2018)

PubMed id: 29722962

Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes.

S.A.Andrei, F.A.Meijer, J.F.Neves, L.Brunsveld, I.Landrieu, C.Ottmann, L.G.Milroy.

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.