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基本情報
登録情報 | データベース: PDB / ID: 8u8a | ||||||
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タイトル | Cryo-EM structure of LRRK2 bound to type II inhibitor ponatinib | ||||||
![]() | Leucine-rich repeat serine/threonine-protein kinase 2 | ||||||
![]() | HYDROLASE/HYDROLASE INHIBITOR / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / type II inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex | ||||||
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 / regulation of locomotion / protein kinase A binding / 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 / dendrite cytoplasm / excitatory postsynaptic potential / 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 / 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 / peptidyl-threonine phosphorylation / 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 | ![]() | ||||||
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: 3.4 Å | ||||||
![]() | Zhu, H. / Sun, J. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM. 著者: Hanwen Zhu / Patricia Hixson / Wen Ma / Ji Sun / ![]() 要旨: LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being ...LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design. | ||||||
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 661.4 KB | 表示 | ![]() |
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-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 | ![]() | 95.3 KB | 表示 | |
CIF形式データ | ![]() | 145.9 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 | ![]() 42019MC ![]() 8fo7C ![]() 8u7hC ![]() 8u7lC ![]() 8u8bC 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 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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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: 286427.656 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 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 #2: 化合物 | #3: 化合物 | 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: 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: LRRK2-ponatinib / タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT |
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分子量 | 値: 286 kDa/nm / 実験値: YES |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 8 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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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 / 最大 デフォーカス(公称値): 1800 nm / 最小 デフォーカス(公称値): 600 nm |
撮影 | 電子線照射量: 68.11 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
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解析
EMソフトウェア |
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CTF補正 | タイプ: NONE | ||||||||||||
3次元再構成 | 解像度: 3.4 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 75849 / 対称性のタイプ: POINT |