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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 8fo8 | ||||||
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タイトル | Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 dimer state | ||||||
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![]() | HYDROLASE / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / Rab GTPases / Activation | ||||||
機能・相同性 | ![]() protein localization to ciliary membrane / 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 ...protein localization to ciliary membrane / 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 / cytoplasmic side of mitochondrial outer membrane / mitochondrion localization / co-receptor binding / modulation by host of viral process / 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 / RAB geranylgeranylation / positive regulation of intracellular protein transport / multivesicular body, internal vesicle / regulation of protein kinase A signaling / striatum development / melanosome organization / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / cellular response to dopamine / protein localization to membrane / cis-Golgi network / positive regulation of protein autoubiquitination / endoplasmic reticulum organization / presynaptic cytosol / retrograde transport, endosome to Golgi / positive regulation of programmed cell death / Wnt signalosome / regulation of canonical Wnt signaling pathway / GTP metabolic process / cellular detoxification / negative regulation of protein processing / vacuole / 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 / regulation of synaptic vesicle exocytosis / PTK6 promotes HIF1A stabilization / clathrin binding / neuromuscular junction development / negative regulation of macroautophagy / intracellular vesicle / dynein complex binding / positive regulation of receptor recycling / lysosome organization / regulation of mitochondrial fission / intracellular distribution of mitochondria / positive regulation of T cell receptor signaling pathway / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / Golgi organization / kinesin binding / endoplasmic reticulum exit site / microvillus / Rho protein signal transduction / MAP kinase kinase kinase activity / positive regulation of protein kinase activity / canonical Wnt signaling pathway / endomembrane system / cellular response to manganese ion / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of autophagy / JNK cascade / regulation of synaptic transmission, glutamatergic / synapse assembly / T cell activation / cellular response to starvation / dendrite cytoplasm / tubulin binding / GTPase activator activity 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: 3.88 Å | ||||||
![]() | Zhu, H. / Sun, J. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. 著者: Hanwen Zhu / Francesca Tonelli / Martin Turk / Alan Prescott / Dario R Alessi / Ji Sun / ![]() ![]() 要旨: Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles ...Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment. #1: ![]() タイトル: Structural basis of human LRRK2 membrane recruitment and activation 著者: Zhu, H. / Tonelli, F. / Alessi, D. / Sun, J. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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PDBx/mmCIF形式 | ![]() | 820.9 KB | 表示 | ![]() |
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PDB形式 | ![]() | 655.5 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 | ![]() | 131.9 KB | 表示 | |
CIF形式データ | ![]() | 201.1 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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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: 20239.076 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() #2: 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 #3: 化合物 | #4: 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: Rab29-LRRK2 / タイプ: COMPLEX / Entity ID: #1-#2 / 由来: RECOMBINANT |
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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: 58.8 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: 3.88 Å / 解像度の算出法: OTHER / 粒子像の数: 96502 / 対称性のタイプ: POINT |