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基本情報
登録情報 | データベース: PDB / ID: 8tzh | ||||||
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タイトル | Structure of full-length LRRK2 bound to MLi-2 (I2020T mutant) | ||||||
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![]() | PROTEIN BINDING / GtPase / kinase / inhibitors | ||||||
機能・相同性 | ![]() peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / tangential migration from the subventricular zone to the olfactory bulb ...peroxidase inhibitor activity / caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / negative regulation of late endosome to lysosome transport / regulation of synaptic vesicle transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / positive regulation of dopamine receptor signaling pathway / regulation of lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / amphisome / mitochondrion localization / cytoplasmic side of mitochondrial outer membrane / co-receptor binding / regulation of retrograde transport, endosome to Golgi / negative regulation of excitatory postsynaptic potential / regulation of dopamine receptor signaling pathway / negative regulation of autophagosome assembly / positive regulation of microglial cell activation / neuron projection arborization / positive regulation of synaptic vesicle endocytosis / JUN kinase kinase kinase activity / olfactory bulb development / regulation of protein kinase A signaling / multivesicular body, internal vesicle / striatum development / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / cellular response to dopamine / presynaptic cytosol / positive regulation of protein autoubiquitination / endoplasmic reticulum organization / positive regulation of programmed cell death / Wnt signalosome / regulation of canonical Wnt signaling pathway / GTP metabolic process / negative regulation of protein processing / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / negative regulation of GTPase activity / exploration behavior / autolysosome / protein kinase A binding / regulation of locomotion / Golgi-associated vesicle / neuromuscular junction development / regulation of synaptic vesicle exocytosis / PTK6 promotes HIF1A stabilization / clathrin binding / negative regulation of macroautophagy / regulation of mitochondrial fission / lysosome organization / intracellular distribution of mitochondria / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / Golgi organization / endoplasmic reticulum exit site / microvillus / Rho protein signal transduction / MAP kinase kinase kinase activity / positive regulation of protein kinase activity / canonical Wnt signaling pathway / cellular response to manganese ion / positive regulation of autophagy / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / JNK cascade / regulation of synaptic transmission, glutamatergic / excitatory postsynaptic potential / dendrite cytoplasm / cellular response to starvation / tubulin binding / mitochondrion organization / GTPase activator activity / neuron projection morphogenesis / SNARE binding / negative regulation of protein phosphorylation / negative regulation of protein binding / positive regulation of protein ubiquitination / regulation of autophagy / regulation of membrane potential / determination of adult lifespan / mitochondrial membrane / calcium-mediated signaling / peptidyl-threonine phosphorylation / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / positive regulation of MAP kinase activity / regulation of protein stability / protein localization / trans-Golgi network 類似検索 - 分子機能 | ||||||
生物種 | synthetic construct (人工物)![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.9 Å | ||||||
![]() | Sanz-Murillo, M. / Villagran-Suarez, A. / Alegrio Louro, J. / Leschziner, A. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures. 著者: Marta Sanz Murillo / Amalia Villagran Suarez / Verena Dederer / Deep Chatterjee / Jaime Alegrio Louro / Stefan Knapp / Sebastian Mathea / Andres E Leschziner / ![]() ![]() 要旨: Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with ...Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-electron microscopy structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type I inhibitor MLi-2 and the broad-spectrum type II inhibitor GZD-824. Our structures revealed an active-like LRRK2 kinase in the type I inhibitor complex, and an inactive DYG-out in the type II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structures provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 304.6 KB | 表示 | ![]() |
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PDB形式 | ![]() | 220.8 KB | 表示 | ![]() |
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その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.5 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.5 MB | 表示 | |
XML形式データ | ![]() | 63.7 KB | 表示 | |
CIF形式データ | ![]() | 95.2 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 41759MC ![]() 8txzC ![]() 8tyqC ![]() 8tzbC ![]() 8tzcC ![]() 8tzeC ![]() 8tzfC ![]() 8tzgC C: 同じ文献を引用 ( M: このデータのモデリングに利用したマップデータ |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 19766.912 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) synthetic construct (人工物) / 発現宿主: ![]() ![]() |
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#2: タンパク質 | 分子量: 286462.781 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q5S007, non-specific serine/threonine protein kinase, 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 |
#3: 化合物 | ChemComp-A1N / ( |
#4: 化合物 | ChemComp-GDP / |
研究の焦点であるリガンドがあるか | Y |
-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: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: Full-length LRRK2 (I2020T mutation) bound to MLi-2 / タイプ: COMPLEX / Entity ID: #1-#2 / 由来: RECOMBINANT | |||||||||||||||||||||||||||||||||||
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分子量 | 値: 0.286 MDa / 実験値: YES | |||||||||||||||||||||||||||||||||||
由来(天然) | 生物種: ![]() | |||||||||||||||||||||||||||||||||||
由来(組換発現) | 生物種: ![]() ![]() | |||||||||||||||||||||||||||||||||||
緩衝液 | pH: 7.4 | |||||||||||||||||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 1.43 mg/ml / 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: UltrAuFoil R2/2 | |||||||||||||||||||||||||||||||||||
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: 277.15 K 詳細: Blot force = 3 Blot time = 4 seconds Wait time = 20 seconds |
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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: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 130000 X / 最大 デフォーカス(公称値): 4000 nm / 最小 デフォーカス(公称値): 1000 nm / Cs: 2.7 mm / C2レンズ絞り径: 50 µm |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 平均露光時間: 11 sec. / 電子線照射量: 55 e/Å2 フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 撮影したグリッド数: 1 / 実像数: 10488 |
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解析
EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 220313 | ||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 102649 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: AB INITIO MODEL / 空間: REAL | ||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 7LHW PDB chain-ID: A / Accession code: 7LHW / Chain residue range: 1-2527 / Pdb chain residue range: 1-2527 / Source name: PDB / タイプ: experimental model | ||||||||||||||||||||||||||||||||||||
拘束条件 |
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