+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-42148 | |||||||||
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タイトル | Structure of human constitutive 20S proteasome complexed with the inhibitor TDI-8304 | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | 20S proteasome (プロテアソーム) / inhibitor (酵素阻害剤) / human (ヒト) / complex / HYDROLASE-HYDROLASE INHIBITOR complex | |||||||||
機能・相同性 | 機能・相同性情報 purine ribonucleoside triphosphate binding / regulation of endopeptidase activity / Regulation of ornithine decarboxylase (ODC) / proteasome core complex / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / immune system process / myofibril / NF-kappaB binding / proteasome endopeptidase complex ...purine ribonucleoside triphosphate binding / regulation of endopeptidase activity / Regulation of ornithine decarboxylase (ODC) / proteasome core complex / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / immune system process / myofibril / NF-kappaB binding / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / negative regulation of inflammatory response to antigenic stimulus / response to organonitrogen compound / proteasome complex / proteolysis involved in protein catabolic process / sarcomere / Regulation of activated PAK-2p34 by proteasome mediated degradation / ciliary basal body / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / TNFR2 non-canonical NF-kB pathway / Assembly of the pre-replicative complex / Vpu mediated degradation of CD4 / proteasomal protein catabolic process / Degradation of DVL / P-body / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Dectin-1 mediated noncanonical NF-kB signaling / Hh mutants are degraded by ERAD / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Degradation of AXIN / Defective CFTR causes cystic fibrosis / Degradation of GLI1 by the proteasome / lipopolysaccharide binding / Hedgehog ligand biogenesis / Activation of NF-kappaB in B cells / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / G2/M Checkpoints / Vif-mediated degradation of APOBEC3G / Autodegradation of the E3 ubiquitin ligase COP1 / Hedgehog 'on' state / Regulation of RUNX3 expression and activity / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / MAPK6/MAPK4 signaling / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / response to virus / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / ABC-family proteins mediated transport / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / response to organic cyclic compound / CDK-mediated phosphorylation and removal of Cdc6 / CLEC7A (Dectin-1) signaling / SCF(Skp2)-mediated degradation of p27/p21 / Regulation of expression of SLITs and ROBOs / nuclear matrix / FCERI mediated NF-kB activation / Regulation of PTEN stability and activity / Interleukin-1 signaling / Orc1 removal from chromatin / Regulation of RAS by GAPs / Separation of Sister Chromatids / Regulation of RUNX2 expression and activity / The role of GTSE1 in G2/M progression after G2 checkpoint / UCH proteinases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / Downstream TCR signaling / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / positive regulation of NF-kappaB transcription factor activity / peptidase activity / ER-Phagosome pathway / regulation of inflammatory response / postsynapse / proteasome-mediated ubiquitin-dependent protein catabolic process / secretory granule lumen / endopeptidase activity / response to oxidative stress / ficolin-1-rich granule lumen / nuclear body / リボソーム / Ub-specific processing proteases / cadherin binding / intracellular membrane-bounded organelle / 中心体 / シナプス / ubiquitin protein ligase binding / Neutrophil degranulation / ミトコンドリア / タンパク質分解 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.04 Å | |||||||||
データ登録者 | Hsu H-C / Li H | |||||||||
資金援助 | 米国, 1件
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引用 | ジャーナル: Nat Commun / 年: 2023 タイトル: Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors. 著者: Hao-Chi Hsu / Daqiang Li / Wenhu Zhan / Jianxiang Ye / Yi Jing Liu / Annie Leung / Junling Qin / Benigno Crespo / Francisco-Javier Gamo / Hao Zhang / Liwang Cui / Alison Roth / Laura A ...著者: Hao-Chi Hsu / Daqiang Li / Wenhu Zhan / Jianxiang Ye / Yi Jing Liu / Annie Leung / Junling Qin / Benigno Crespo / Francisco-Javier Gamo / Hao Zhang / Liwang Cui / Alison Roth / Laura A Kirkman / Huilin Li / Gang Lin / 要旨: The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with ...The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6 with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_42148.map.gz | 157.1 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-42148-v30.xml emd-42148.xml | 34 KB 34 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_42148_fsc.xml | 11.5 KB | 表示 | FSCデータファイル |
画像 | emd_42148.png | 119.7 KB | ||
マスクデータ | emd_42148_msk_1.map | 166.4 MB | マスクマップ | |
Filedesc metadata | emd-42148.cif.gz | 9 KB | ||
その他 | emd_42148_half_map_1.map.gz emd_42148_half_map_2.map.gz | 154.3 MB 154.3 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-42148 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-42148 | 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_42148.map.gz / 形式: CCP4 / 大きさ: 166.4 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 0.828 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-マスク #1
ファイル | emd_42148_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 |
-ハーフマップ: #2
ファイル | emd_42148_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_42148_half_map_2.map | ||||||||||||
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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 : Human 20S constitutive proteasome complexed with inhibitor TDI-8304
+超分子 #1: Human 20S constitutive proteasome complexed with inhibitor TDI-8304
+分子 #1: Proteasome subunit alpha type-6
+分子 #2: Proteasome subunit alpha type-2
+分子 #3: Proteasome subunit alpha type-4
+分子 #4: Proteasome subunit alpha type-7
+分子 #5: Proteasome subunit alpha type-5
+分子 #6: Proteasome subunit alpha type-1
+分子 #7: Proteasome subunit alpha type-3
+分子 #8: Proteasome subunit beta type-6
+分子 #9: Proteasome subunit beta type-7
+分子 #10: Proteasome subunit beta type-3
+分子 #11: Proteasome subunit beta type-2
+分子 #12: Proteasome subunit beta type-5
+分子 #13: Proteasome subunit beta type-1
+分子 #14: Proteasome subunit beta type-4
+分子 #15: (7S,10S,13S)-N-cyclopentyl-10-[2-(morpholin-4-yl)ethyl]-9,12-diox...
+分子 #16: water
-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
濃度 | 4 mg/mL | ||||||||||||||||||
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緩衝液 | pH: 7.5 構成要素:
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凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 279 K / 装置: FEI VITROBOT MARK IV |
-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: 100.0 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): 1.4000000000000001 µm 最小 デフォーカス(公称値): 1.0 µm / 倍率(公称値): 105000 |
特殊光学系 | エネルギーフィルター - 名称: GIF Bioquantum / エネルギーフィルター - スリット幅: 20 eV |
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 K3 BIOQUANTUM (6k x 4k) デジタル化 - サイズ - 横: 11520 pixel / デジタル化 - サイズ - 縦: 8184 pixel / 撮影したグリッド数: 1 / 実像数: 16114 / 平均露光時間: 1.0 sec. / 平均電子線量: 58.0 e/Å2 |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |