7B3J
Dynamic complex between all-D-enantiomeric peptide D3 with wild-type amyloid precursor protein 672-726 fragment (amyloid beta 1-55)
Summary for 7B3J
| Entry DOI | 10.2210/pdb7b3j/pdb |
| Related | 1ze7 2llm |
| NMR Information | BMRB: 34577 |
| Descriptor | Isoform L-APP677 of Amyloid-beta precursor protein, D3 all D-enantimeric peptide (2 entities in total) |
| Functional Keywords | d-peptide, amyloid-beta, complex, transmembrane, protein binding |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 7597.91 |
| Authors | Bocharov, E.V.,Volynsky, P.E.,Okhrimenko, I.S.,Urban, A.S. (deposition date: 2020-12-01, release date: 2021-01-13, Last modification date: 2021-12-08) |
| Primary citation | Bocharov, E.V.,Gremer, L.,Urban, A.S.,Okhrimenko, I.S.,Volynsky, P.E.,Nadezhdin, K.D.,Bocharova, O.V.,Kornilov, D.A.,Zagryadskaya, Y.A.,Kamynina, A.V.,Kuzmichev, P.K.,Kutzsche, J.,Bolakhrif, N.,Muller-Schiffmann, A.,Dencher, N.A.,Arseniev, A.S.,Efremov, R.G.,Gordeliy, V.I.,Willbold, D. All - d - Enantiomeric Peptide D3 Designed for Alzheimer's Disease Treatment Dynamically Interacts with Membrane-Bound Amyloid-beta Precursors. J.Med.Chem., 64:16464-16479, 2021 Cited by PubMed Abstract: Alzheimer's disease (AD) is a severe neurodegenerative pathology with no effective treatment known. Toxic amyloid-β peptide (Aβ) oligomers play a crucial role in AD pathogenesis. AlldEnantiomeric peptide D3 and its derivatives were developed to disassemble and destroy cytotoxic Aβ aggregates. One of the D3-like compounds is approaching phase II clinical trials; however, high-resolution details of its disease-preventing or pharmacological actions are not completely clear. We demonstrate that peptide D3 stabilizing Aβ monomer dynamically interacts with the extracellular juxtamembrane region of a membrane-bound fragment of an amyloid precursor protein containing the Aβ sequence. MD simulations based on NMR measurement results suggest that D3 targets the amyloidogenic region, not compromising its α-helicity and preventing intermolecular hydrogen bonding, thus creating prerequisites for inhibition of early steps of Aβ conversion into β-conformation and its toxic oligomerization. An enhanced understanding of the D3 action molecular mechanism facilitates development of effective AD treatment and prevention strategies. PubMed: 34739758DOI: 10.1021/acs.jmedchem.1c00632 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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