7OW1
Crystal Structure of TAP01 in complex with amyloid beta peptide
Summary for 7OW1
| Entry DOI | 10.2210/pdb7ow1/pdb |
| Descriptor | Amyloid-beta precursor protein, TAP01 family antibody heavy chain, TAP01 family antibody light chain, ... (5 entities in total) |
| Functional Keywords | alzheimer's disease, immune system |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 3 |
| Total formula weight | 48446.81 |
| Authors | Hall, G.,Cowan, R.,Carr, M.D. (deposition date: 2021-06-16, release date: 2022-06-29, Last modification date: 2024-10-16) |
| Primary citation | Bakrania, P.,Hall, G.,Bouter, Y.,Bouter, C.,Beindorff, N.,Cowan, R.,Davies, S.,Price, J.,Mpamhanga, C.,Love, E.,Matthews, D.,Carr, M.D.,Bayer, T.A. Discovery of a novel pseudo beta-hairpin structure of N-truncated amyloid-beta for use as a vaccine against Alzheimer's disease. Mol Psychiatry, 27:840-848, 2022 Cited by PubMed Abstract: One of the hallmarks of Alzheimer's disease (AD) are deposits of amyloid-beta (Aβ) protein in amyloid plaques in the brain. The Aβ peptide exists in several forms, including full-length Aβ1-42 and Aβ1-40 - and the N-truncated species, pyroglutamate Aβ3-42 and Aβ4-42, which appear to play a major role in neurodegeneration. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aβ species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aβ3-14, we identified a novel pseudo β-hairpin structure in the N-terminal region of Aβ and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Aβ1-14 (N-Truncated Amyloid Peptide AntibodieS; the 'TAPAS' vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aβ, which offers new routes for active and passive immunisation against AD. PubMed: 34776512DOI: 10.1038/s41380-021-01385-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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