+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-12095 | |||||||||
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タイトル | Cryo-EM structure of mitochondrial complex I from Mus musculus inhibited by IACS-2858 at 3.0 A | |||||||||
マップデータ | Globally sharpened and filtered map from RELION's PostProcess tool | |||||||||
試料 |
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機能・相同性 | 機能・相同性情報 response to injury involved in regulation of muscle adaptation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / reproductive system development / Mitochondrial protein import / Respiratory electron transport / Glyoxylate metabolism and glycine degradation / RHOG GTPase cycle / respiratory system process / protein insertion into mitochondrial inner membrane ...response to injury involved in regulation of muscle adaptation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / reproductive system development / Mitochondrial protein import / Respiratory electron transport / Glyoxylate metabolism and glycine degradation / RHOG GTPase cycle / respiratory system process / protein insertion into mitochondrial inner membrane / response to light intensity / blastocyst hatching / circulatory system development / ubiquinone-6 biosynthetic process / cellular response to oxygen levels / iron-sulfur cluster assembly complex / psychomotor behavior / mitochondrial large ribosomal subunit binding / gliogenesis / neural precursor cell proliferation / [2Fe-2S] cluster assembly / mitochondrial respirasome / NADH dehydrogenase activity / cardiac muscle tissue development / oxygen sensor activity / respiratory chain complex I / 細胞呼吸 / adult walking behavior / negative regulation of non-canonical NF-kappaB signal transduction / ubiquinone binding / cellular response to glucocorticoid stimulus / positive regulation of mitochondrial membrane potential / acyl binding / response to hydroperoxide / mitochondrial ribosome / electron transport coupled proton transport / iron-sulfur cluster assembly / mitochondrial ATP synthesis coupled electron transport / acyl carrier activity / mitochondrial translation / adult behavior / dopamine metabolic process / NADH:ユビキノン還元酵素 (水素イオン輸送型) / positive regulation of ATP biosynthetic process / proton motive force-driven mitochondrial ATP synthesis / mitochondrial respiratory chain complex I / apoptotic mitochondrial changes / mitochondrial respiratory chain complex I assembly / mitochondrial electron transport, NADH to ubiquinone / 電子伝達系 / NADH dehydrogenase (ubiquinone) activity / neuron development / quinone binding / ATP synthesis coupled electron transport / cellular response to interferon-beta / negative regulation of intrinsic apoptotic signaling pathway / 細胞呼吸 / ATP metabolic process / negative regulation of reactive oxygen species biosynthetic process / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / response to cAMP / response to organonitrogen compound / クエン酸回路 / ionotropic glutamate receptor binding / respiratory electron transport chain / reactive oxygen species metabolic process / 視覚 / Neutrophil degranulation / cerebellum development / mitochondrion organization / 神経発生 / response to hormone / response to cocaine / fatty acid metabolic process / regulation of mitochondrial membrane potential / response to nicotine / synaptic membrane / muscle contraction / kidney development / apoptotic signaling pathway / ミトコンドリア / sensory perception of sound / regulation of protein phosphorylation / brain development / multicellular organism growth / response to hydrogen peroxide / ミトコンドリア / 2 iron, 2 sulfur cluster binding / negative regulation of cell growth / response to organic cyclic compound / 認識 / 概日リズム / positive regulation of protein catabolic process / NAD binding / positive regulation of fibroblast proliferation / FMN binding / 髄鞘 / nervous system development / 4 iron, 4 sulfur cluster binding 類似検索 - 分子機能 | |||||||||
生物種 | Mus musculus (ハツカネズミ) / Mouse (ネズミ) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.04 Å | |||||||||
データ登録者 | Chung I / Hirst J | |||||||||
資金援助 | 英国, 2件
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引用 | ジャーナル: Sci Adv / 年: 2021 タイトル: Cork-in-bottle mechanism of inhibitor binding to mammalian complex I. 著者: Injae Chung / Riccardo Serreli / Jason B Cross / M Emilia Di Francesco / Joseph R Marszalek / Judy Hirst / 要旨: Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia- ...Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo-electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design. | |||||||||
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 | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_12095.map.gz | 324.9 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-12095-v30.xml emd-12095.xml | 68.1 KB 68.1 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_12095_fsc.xml | 15.9 KB | 表示 | FSCデータファイル |
画像 | emd_12095.png | 167.2 KB | ||
マスクデータ | emd_12095_msk_1.map | 347.6 MB | マスクマップ | |
その他 | emd_12095_additional_1.map.gz emd_12095_half_map_1.map.gz emd_12095_half_map_2.map.gz | 277.8 MB 278 MB 277.5 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-12095 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12095 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_12095.map.gz / 形式: CCP4 / 大きさ: 347.6 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | Globally sharpened and filtered map from RELION's PostProcess tool | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.055 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-マスク #1
ファイル | emd_12095_msk_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-追加マップ: Full map from RELION's 3D Refinement tool (unsharpened...
ファイル | emd_12095_additional_1.map | ||||||||||||
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注釈 | Full map from RELION's 3D Refinement tool (unsharpened and unfiltered) | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Half map 1 from RELION's 3D Refinement tool...
ファイル | emd_12095_half_map_1.map | ||||||||||||
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注釈 | Half map 1 from RELION's 3D Refinement tool (unsharpened and unfiltered) | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: Half map 2 from RELION's 3D Refinement tool...
ファイル | emd_12095_half_map_2.map | ||||||||||||
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注釈 | Half map 2 from RELION's 3D Refinement tool (unsharpened and unfiltered) | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
+全体 : Respiratory complex I
+超分子 #1: Respiratory complex I
+分子 #1: NADH-ubiquinone oxidoreductase chain 3
+分子 #2: NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial
+分子 #3: NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial
+分子 #4: NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial
+分子 #5: NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial
+分子 #6: NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial
+分子 #7: NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial
+分子 #8: NADH-ubiquinone oxidoreductase chain 1
+分子 #9: NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial
+分子 #10: NADH-ubiquinone oxidoreductase chain 6
+分子 #11: NADH-ubiquinone oxidoreductase chain 4L
+分子 #12: NADH-ubiquinone oxidoreductase chain 5
+分子 #13: NADH-ubiquinone oxidoreductase chain 4
+分子 #14: NADH-ubiquinone oxidoreductase chain 2
+分子 #15: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mi...
+分子 #16: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mit...
+分子 #17: NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial
+分子 #18: NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial
+分子 #19: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2
+分子 #20: Acyl carrier protein, mitochondrial
+分子 #21: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5
+分子 #22: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6
+分子 #23: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8
+分子 #24: MCG5603
+分子 #25: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13
+分子 #26: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1
+分子 #27: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3
+分子 #28: NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial
+分子 #29: NADH dehydrogenase [ubiquinone] 1 subunit C2
+分子 #30: NADH dehydrogenase [ubiquinone] iron-sulfur protein 5
+分子 #31: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1
+分子 #32: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mit...
+分子 #33: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mito...
+分子 #34: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6
+分子 #35: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mito...
+分子 #36: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3
+分子 #37: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mito...
+分子 #38: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4
+分子 #39: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9
+分子 #40: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7
+分子 #41: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10
+分子 #42: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12
+分子 #43: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7
+分子 #44: NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial
+分子 #45: IRON/SULFUR CLUSTER
+分子 #46: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+分子 #47: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE
+分子 #48: FE2/S2 (INORGANIC) CLUSTER
+分子 #49: FLAVIN MONONUCLEOTIDE
+分子 #50: 1-[[3-(4-methylsulfonylpiperidin-1-yl)phenyl]methyl]-5-[3-[4-(tri...
+分子 #51: CARDIOLIPIN
+分子 #52: ADENOSINE-5'-TRIPHOSPHATE
+分子 #53: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
+分子 #54: ZINC ION
+分子 #55: ~{S}-[2-[3-[[(2~{R})-3,3-dimethyl-2-oxidanyl-4-phosphonooxy-butan...
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 7.14 構成要素:
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グリッド | 材質: GOLD 詳細: THE GRID WAS TREATED FOR 48 HOURS IN AN ANAEROBIC GLOVEBOX IN ETHANOL CONTAINING 5MM 11-MERCAPTOUNDECYLHEXAETHYLENEGLYCOL, WASHED THREE TIMES IN ETHANOL AND DRIED PRIOR TO USE. | ||||||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 277 K / 装置: FEI VITROBOT MARK IV / 詳細: blot for 10 seconds before plunging. |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | C2レンズ絞り径: 70.0 µm / 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / 最大 デフォーカス(公称値): 2.7 µm / 最小 デフォーカス(公称値): 1.5 µm / 倍率(公称値): 130000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
撮影 | フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 検出モード: COUNTING / 撮影したグリッド数: 2 / 平均電子線量: 52.0 e/Å2 |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |