9B4K
Filament of D-TLKIVWR, a D-peptide that disaggregates Alzheimer's Paired Helical Filaments, determined by Cryo-EM
Summary for 9B4K
| Entry DOI | 10.2210/pdb9b4k/pdb |
| Related | 9B4I |
| EMDB information | 44183 |
| Descriptor | DTH-DLE-DLY-DIL-DVA-DTR-DAR (1 entity in total) |
| Functional Keywords | alzheimer's disease, tau, fibril, cryo-em, helix, unknown function |
| Biological source | synthetic construct |
| Total number of polymer chains | 52 |
| Total formula weight | 47639.38 |
| Authors | Hou, K.,Ge, P.,Sawaya, M.R.,Eisenberg, D.S. (deposition date: 2024-03-20, release date: 2025-03-12, Last modification date: 2025-07-23) |
| Primary citation | Hou, K.,Ge, P.,Sawaya, M.R.,Lutter, L.,Dolinsky, J.L.,Yang, Y.,Jiang, Y.X.,Boyer, D.R.,Cheng, X.,Pi, J.,Zhang, J.,Lu, J.,Abskharon, R.,Yang, S.,Yu, Z.,Feigon, J.,Eisenberg, D.S. How short peptides disassemble tau fibrils in Alzheimer's disease. Nature, 2025 Cited by PubMed Abstract: Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD). Previously, we found that in vitro, the D-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like ('mock-amyloid') fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases. PubMed: 40634605DOI: 10.1038/s41586-025-09244-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.7 Å) |
Structure validation
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