+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8fug | |||||||||
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タイトル | Alzheimer's disease paired-helical filament in complex with PET tracer GTP-1 | |||||||||
要素 | Microtubule-associated protein tauタウタンパク質 | |||||||||
キーワード | PROTEIN FIBRIL / Neurodegeneration (神経変性疾患) / Positron Emission Tomography / Filament / Alzheimer's disease (アルツハイマー病) | |||||||||
機能・相同性 | 機能・相同性情報 plus-end-directed organelle transport along microtubule / 軸索輸送 / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / 軸索輸送 / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / 微小管 / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / glial cell projection / negative regulation of mitochondrial membrane potential / apolipoprotein binding / protein polymerization / negative regulation of mitochondrial fission / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / supramolecular fiber organization / stress granule assembly / regulation of cellular response to heat / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / positive regulation of microtubule polymerization / axon cytoplasm / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / synapse assembly / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / response to lead ion / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / 記憶 / cellular response to reactive oxygen species / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / activation of cysteine-type endopeptidase activity involved in apoptotic process / neuron projection development / microtubule cytoskeleton / cell-cell signaling / protein-macromolecule adaptor activity / actin binding / single-stranded DNA binding / cellular response to heat / cell body / protein-folding chaperone binding / 成長円錐 / microtubule binding / double-stranded DNA binding / 微小管 / sequence-specific DNA binding / amyloid fibril formation / 樹状突起スパイン / learning or memory / nuclear speck / neuron projection / 脂質ラフト / 神経繊維 / negative regulation of gene expression / neuronal cell body / DNA damage response / 樹状突起 / protein kinase binding / enzyme binding / ミトコンドリア / DNA binding 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 電子顕微鏡法 / らせん対称体再構成法 / クライオ電子顕微鏡法 / 解像度: 2.7 Å | |||||||||
データ登録者 | Merz, G.E. / Tse, E. / Southworth, D.R. | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Nat Commun / 年: 2023 タイトル: Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments. 著者: Gregory E Merz / Matthew J Chalkley / Sophia K Tan / Eric Tse / Joanne Lee / Stanley B Prusiner / Nick A Paras / William F DeGrado / Daniel R Southworth / 要旨: Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease- ...Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-β amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases. | |||||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8fug.cif.gz | 615.9 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8fug.ent.gz | 533.1 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8fug.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/fu/8fug ftp://data.pdbj.org/pub/pdb/validation_reports/fu/8fug | HTTPS FTP |
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-関連構造データ
関連構造データ | 29458MC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
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1 |
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対称性 | らせん対称: (回転対称性: 1 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 23 / Rise per n subunits: 2.37 Å / Rotation per n subunits: 179.45 °) |
-要素
#1: タンパク質 | 分子量: 7940.141 Da / 分子数: 23 / 由来タイプ: 天然 / 由来: (天然) Homo sapiens (ヒト) / 参照: UniProt: P10636 #2: 化合物 | ChemComp-Y9H / ( 研究の焦点であるリガンドがあるか | Y | |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: FILAMENT / 3次元再構成法: らせん対称体再構成法 |
-試料調製
構成要素 | 名称: Alzheimer's tau paired helical filament in complex with PET ligand GTP-1 タイプ: COMPLEX / Entity ID: #1 / 由来: NATURAL | |||||||||||||||
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分子量 | 実験値: NO | |||||||||||||||
由来(天然) | 生物種: Homo sapiens (ヒト) | |||||||||||||||
緩衝液 | pH: 7.4 / 詳細: 20 mM Tris-HCl, pH 7.4, 100 mM NaCl | |||||||||||||||
緩衝液成分 |
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試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | |||||||||||||||
試料支持 | グリッドの材料: GOLD / グリッドのサイズ: 200 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3 | |||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 277 K |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELDBright-field microscopy / 最大 デフォーカス(公称値): 1800 nm / 最小 デフォーカス(公称値): 800 nm / Cs: 2.7 mm |
撮影 | 電子線照射量: 46 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 実像数: 15160 |
電子光学装置 | エネルギーフィルター名称: GIF Bioquantum / エネルギーフィルタースリット幅: 20 eV |
-解析
EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||
らせん対称 | 回転角度/サブユニット: 179.45 ° / 軸方向距離/サブユニット: 2.37 Å / らせん対称軸の対称性: C1 | ||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 380428 | ||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 2.7 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 30199 / 対称性のタイプ: HELICAL |