7B3K

Dynamic complex between all-D-enantiomeric peptide D3 with L723P mutant of amyloid precursor protein (APP) 672-726 fragment (amyloid beta 1-55)

7B3K の概要

• エントリーDOI: 10.2210/pdb7b3k/pdb
• 関連するPDBエントリー: 1ze7 2llm
• NMR情報: BMRB: 34578
• 分子名称: Isoform L-APP677 of Amyloid-beta precursor protein, D3 all D-enantimeric peptide (2 entities in total)
• 機能のキーワード: d3-peptide, all-d-enantiomeric peptide, australian mutation, amyloid-beta, amyloid precursor protein, complex, transmembrane, protein binding
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 7581.87

構造登録者

Bocharov, E.V.,Volynsky, P.E.,Okhrimenko, I.S.,Urban, A.S. (登録日: 2020-12-01, 公開日: 2021-01-13, 最終更新日: 2023-06-14)

主引用文献

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

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: 34739758
DOI: 10.1021/acs.jmedchem.1c00632

実験手法

SOLUTION NMR