+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 5v5c | ||||||||||||
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タイトル | VQIINK, Structure of the amyloid-spine from microtubule associated protein tau Repeat 2 | ||||||||||||
要素 | Microtubule-associated protein tau | ||||||||||||
キーワード | STRUCTURAL PROTEIN / Amyloid / tau / Alzheimer's Disease / tauopathy / MAPT | ||||||||||||
機能・相同性 | 機能・相同性情報 plus-end-directed organelle transport along microtubule / axonal transport / 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 / axonal transport / 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 / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / apolipoprotein binding / glial cell projection / negative regulation of mitochondrial membrane potential / 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 / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / 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 / memory / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / SH3 domain binding / microtubule cytoskeleton organization / 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 / protein-folding chaperone binding / cell body / growth cone / microtubule binding / double-stranded DNA binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding 類似検索 - 分子機能 | ||||||||||||
生物種 | Homo sapiens (ヒト) | ||||||||||||
手法 | 電子線結晶学 / 分子置換 / クライオ電子顕微鏡法 / 解像度: 1.25 Å | ||||||||||||
データ登録者 | Seidler, P.M. / Sawaya, M.R. / Rodriguez, J.A. / Eisenberg, D.S. / Cascio, D. / Boyer, D.R. | ||||||||||||
資金援助 | 米国, 3件
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引用 | ジャーナル: Nat Chem / 年: 2018 タイトル: Structure-based inhibitors of tau aggregation. 著者: P M Seidler / D R Boyer / J A Rodriguez / M R Sawaya / D Cascio / K Murray / T Gonen / D S Eisenberg / 要旨: Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its ...Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau. | ||||||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 5v5c.cif.gz | 13.2 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb5v5c.ent.gz | 5.8 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 5v5c.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
文書・要旨 | 5v5c_validation.pdf.gz | 311 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 5v5c_full_validation.pdf.gz | 310.6 KB | 表示 | |
XML形式データ | 5v5c_validation.xml.gz | 1.2 KB | 表示 | |
CIF形式データ | 5v5c_validation.cif.gz | 1.4 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/v5/5v5c ftp://data.pdbj.org/pub/pdb/validation_reports/v5/5v5c | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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単位格子 |
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-要素
#1: タンパク質・ペプチド | 分子量: 714.873 Da / 分子数: 1 / 断片: Repeat 2 peptide (UNP residues 592-597) / 由来タイプ: 合成 / 由来: (合成) Homo sapiens (ヒト) / 参照: UniProt: P10636*PLUS |
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-実験情報
-実験
実験 | 手法: 電子線結晶学 |
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EM実験 | 試料の集合状態: 3D ARRAY / 3次元再構成法: 電子線結晶学 |
-試料調製
構成要素 | 名称: VQIINK Tau peptide / タイプ: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / 由来: NATURAL |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
EM crystal formation | 温度: 291 K |
緩衝液 | pH: 7 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES / 詳細: 3D micro-crystal |
急速凍結 | 凍結剤: ETHANE |
結晶 | マシュー密度: 1.48 Å3/Da / 溶媒含有率: 17.08 % |
結晶化 | 温度: 291 K / 手法: 蒸気拡散法, ハンギングドロップ法 / pH: 7 / 詳細: 0.29 M lithium nitrate, 24% PEG3350 |
-データ収集
顕微鏡 | モデル: FEI TECNAI 20 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 200 kV / 照射モード: FLOOD BEAM | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
電子レンズ | モード: DIFFRACTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
撮影 | 電子線照射量: 0.1 e/Å2 フィルム・検出器のモデル: TVIPS TEMCAM-F416 (4k x 4k) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM回折 | カメラ長: 730 mm | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM回折 シェル | 解像度: 1.25→1.31 Å / フーリエ空間範囲: 71.6 % / 多重度: 2.5 / 構造因子数: 106 / 位相残差: 0.1 ° | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM回折 統計 | 詳細: This is a crystallography experiment. Phases were not measured. フーリエ空間範囲: 86.8 % / 再高解像度: 1.25 Å / 測定した強度の数: 5454 / 構造因子数: 1226 / 位相誤差: 0.1 ° / 位相残差: 0.1 ° / 位相誤差の除外基準: 0.1 / Rmerge: 23.9 / Rsym: 23.9 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
回折 | 平均測定温度: 100 K | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
放射光源 | 由来: ELECTRON MICROSCOPE / タイプ: TECNAI F20 TEM / 波長: 0.0251 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
検出器 | タイプ: TVIPS TEMCAM-F416 / 検出器: CMOS / 日付: 2016年8月25日 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
放射波長 | 波長: 0.0251 Å / 相対比: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 | 解像度: 1.25→10.18 Å / Num. obs: 1226 / % possible obs: 86.8 % / Observed criterion σ(I): -3 / 冗長度: 4.449 % / Biso Wilson estimate: 5.87 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.239 / Rrim(I) all: 0.265 / Χ2: 0.821 / Net I/σ(I): 3.58 / Num. measured all: 5454 / Scaling rejects: 5 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 シェル | Diffraction-ID: 1
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-位相決定
位相決定 | 手法: 分子置換 |
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-解析
ソフトウェア |
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EMソフトウェア |
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EM 3D crystal entity | ∠α: 90 ° / ∠β: 90 ° / ∠γ: 90 ° / A: 20.36 Å / B: 43.22 Å / C: 4.82 Å / 空間群名: P21212 / 空間群番号: 18 | ||||||||||||||||||||||||
CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
3次元再構成 | 解像度の算出法: DIFFRACTION PATTERN/LAYERLINES / 対称性のタイプ: 3D CRYSTAL | ||||||||||||||||||||||||
精密化 | 構造決定の手法: 分子置換 / 解像度: 1.25→10.18 Å / Cor.coef. Fo:Fc: 0.9086 / Cor.coef. Fo:Fc free: 0.9428 / SU R Cruickshank DPI: 0.072 / 交差検証法: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.067 / SU Rfree Blow DPI: 0.074 / SU Rfree Cruickshank DPI: 0.07
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原子変位パラメータ | Biso max: 49.96 Å2 / Biso mean: 15.3 Å2 / Biso min: 3 Å2
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LS精密化 シェル | 解像度: 1.25→1.4 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
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