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- EMDB-42603: Human p97/VCP structure with a triazole inhibitor (NSC799462/hexamer) -
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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Human p97/VCP structure with a triazole inhibitor (NSC799462/hexamer) | |||||||||
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![]() | AAA+ ATPase / p97 / VCP / triazole / allosteric inhibition / MOTOR PROTEIN | |||||||||
機能・相同性 | ![]() : / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control / cellular response to arsenite ion / BAT3 complex binding / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / cytoplasm protein quality control ...: / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control / cellular response to arsenite ion / BAT3 complex binding / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / cytoplasm protein quality control / positive regulation of protein K63-linked deubiquitination / positive regulation of oxidative phosphorylation / : / aggresome assembly / mitotic spindle disassembly / deubiquitinase activator activity / regulation of protein localization to chromatin / ubiquitin-modified protein reader activity / VCP-NPL4-UFD1 AAA ATPase complex / vesicle-fusing ATPase / cellular response to misfolded protein / negative regulation of protein localization to chromatin / positive regulation of mitochondrial membrane potential / K48-linked polyubiquitin modification-dependent protein binding / regulation of aerobic respiration / retrograde protein transport, ER to cytosol / stress granule disassembly / regulation of synapse organization / ATPase complex / ubiquitin-specific protease binding / MHC class I protein binding / positive regulation of ATP biosynthetic process / ubiquitin-like protein ligase binding / RHOH GTPase cycle / polyubiquitin modification-dependent protein binding / autophagosome maturation / endoplasmic reticulum to Golgi vesicle-mediated transport / negative regulation of hippo signaling / HSF1 activation / translesion synthesis / interstrand cross-link repair / proteasomal protein catabolic process / ATP metabolic process / Protein methylation / endoplasmic reticulum unfolded protein response / Attachment and Entry / ERAD pathway / lipid droplet / proteasome complex / viral genome replication / Josephin domain DUBs / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / negative regulation of smoothened signaling pathway / macroautophagy / positive regulation of protein-containing complex assembly / Hh mutants are degraded by ERAD / Hedgehog ligand biogenesis / establishment of protein localization / Defective CFTR causes cystic fibrosis / positive regulation of non-canonical NF-kappaB signal transduction / Translesion Synthesis by POLH / ADP binding / ABC-family proteins mediated transport / autophagy / positive regulation of protein catabolic process / cytoplasmic stress granule / Aggrephagy / azurophil granule lumen / KEAP1-NFE2L2 pathway / Ovarian tumor domain proteases / positive regulation of canonical Wnt signaling pathway / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / E3 ubiquitin ligases ubiquitinate target proteins / double-strand break repair / site of double-strand break / Neddylation / cellular response to heat / ubiquitin-dependent protein catabolic process / secretory granule lumen / protein phosphatase binding / regulation of apoptotic process / proteasome-mediated ubiquitin-dependent protein catabolic process / ficolin-1-rich granule lumen / Attachment and Entry / protein ubiquitination / ciliary basal body / protein domain specific binding / DNA repair / intracellular membrane-bounded organelle / lipid binding / ubiquitin protein ligase binding / DNA damage response / Neutrophil degranulation / endoplasmic reticulum membrane / perinuclear region of cytoplasm / glutamatergic synapse / endoplasmic reticulum / protein-containing complex / ATP hydrolysis activity / RNA binding 類似検索 - 分子機能 | |||||||||
生物種 | ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.23 Å | |||||||||
![]() | Nandi P / DeVore K / Chiu P-L | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors. 著者: Purbasha Nandi / Kira DeVore / Feng Wang / Shan Li / Joel D Walker / Thanh Tung Truong / Matthew G LaPorte / Peter Wipf / Heidi Schlager / John McCleerey / William Paquette / Rod Carlo A ...著者: Purbasha Nandi / Kira DeVore / Feng Wang / Shan Li / Joel D Walker / Thanh Tung Truong / Matthew G LaPorte / Peter Wipf / Heidi Schlager / John McCleerey / William Paquette / Rod Carlo A Columbres / Taiping Gan / Yu-Ping Poh / Petra Fromme / Andrew J Flint / Mark Wolf / Donna M Huryn / Tsui-Fen Chou / Po-Lin Chiu / ![]() ![]() 要旨: Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been ...Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications. | |||||||||
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その他 | ![]() ![]() | 164.8 MB 164.8 MB | ||
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文書・要旨 | ![]() | 932.7 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 932.3 KB | 表示 | |
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-関連構造データ
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||||||||||||||||||
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注釈 | Sharpened map. | ||||||||||||||||||||||||||||||||||||
投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.04 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
-ハーフマップ: Half map A.
ファイル | emd_42603_half_map_1.map | ||||||||||||
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注釈 | Half map A. | ||||||||||||
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 B.
ファイル | emd_42603_half_map_2.map | ||||||||||||
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注釈 | Half map B. | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : p97/VCP AAA+ ATPase/NSC799462
全体 | 名称: p97/VCP AAA+ ATPase/NSC799462 |
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要素 |
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-超分子 #1: p97/VCP AAA+ ATPase/NSC799462
超分子 | 名称: p97/VCP AAA+ ATPase/NSC799462 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1 詳細: p97/VCP AAA+ ATPase bound with the triazole NSC799462. |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 536 KDa |
-分子 #1: Transitional endoplasmic reticulum ATPase
分子 | 名称: Transitional endoplasmic reticulum ATPase / タイプ: protein_or_peptide / ID: 1 詳細: The coordinate contains nucleotides ADP and a triazole inhibitor, NSC799462. コピー数: 6 / 光学異性体: LEVO / EC番号: vesicle-fusing ATPase |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 89.43682 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVR NNLRVRLGDV ISIQPCPDVK YGKRIHVLPI DDTVEGITGN LFEVYLKPYF LEAYRPIRKG DIFLVRGGMR A VEFKVVET ...文字列: MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVR NNLRVRLGDV ISIQPCPDVK YGKRIHVLPI DDTVEGITGN LFEVYLKPYF LEAYRPIRKG DIFLVRGGMR A VEFKVVET DPSPYCIVAP DTVIHCEGEP IKREDEEESL NEVGYDDIGG CRKQLAQIKE MVELPLRHPA LFKAIGVKPP RG ILLYGPP GTGKTLIARA VANETGAFFF LINGPEIMSK LAGESESNLR KAFEEAEKNA PAIIFIDELD AIAPKREKTH GEV ERRIVS QLLTLMDGLK QRAHVIVMAA TNRPNSIDPA LRRFGRFDRE VDIGIPDATG RLEILQIHTK NMKLADDVDL EQVA NETHG HVGADLAALC SEAALQAIRK KMDLIDLEDE TIDAEVMNSL AVTMDDFRWA LSQSNPSALR ETVVEVPQVT WEDIG GLED VKRELQELVQ YPVEHPDKFL KFGMTPSKGV LFYGPPGCGK TLLAKAIANE CQANFISIKG PELLTMWFGE SEANVR EIF DKARQAAPCV LFFDELDSIA KARGGNIGDG GGAADRVINQ ILTEMDGMST KKNVFIIGAT NRPDIIDPAI LRPGRLD QL IYIPLPDEKS RVAILKANLR KSPVAKDVDL EFLAKMTNGF SGADLTEICQ RACKLAIRES IESEIRRERE RQTNPSAM E VEEDDPVPEI RRDHFEEAMR FARRSVSDND IRKYEMFAQT LQQSRGFGSF RFPSGNQGGA GPSQGSGGGT GGSVYTEDN DDDLYG UniProtKB: Transitional endoplasmic reticulum ATPase |
-分子 #2: ADENOSINE-5'-DIPHOSPHATE
分子 | 名称: ADENOSINE-5'-DIPHOSPHATE / タイプ: ligand / ID: 2 / コピー数: 12 / 式: ADP |
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分子量 | 理論値: 427.201 Da |
Chemical component information | ![]() ChemComp-ADP: |
-分子 #3: 3-(4-{[(4P)-5-{[(1R)-cyclohex-2-en-1-yl]sulfanyl}-4-(pyridin-3-yl...
分子 | 名称: 3-(4-{[(4P)-5-{[(1R)-cyclohex-2-en-1-yl]sulfanyl}-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]methoxy}-2,6-difluorophenyl)prop-2-yn-1-yl (1-methylpiperidin-4-yl)carbamate タイプ: ligand / ID: 3 / コピー数: 6 / 式: XKM |
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分子量 | 理論値: 594.675 Da |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.4 構成要素:
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グリッド | モデル: C-flat-2/1 / 材質: COPPER / メッシュ: 400 / 支持フィルム - 材質: CARBON / 支持フィルム - トポロジー: HOLEY ARRAY / 支持フィルム - Film thickness: 30 / 前処理 - タイプ: GLOW DISCHARGE / 前処理 - 時間: 15 sec. / 前処理 - 雰囲気: AIR | |||||||||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 90 % / チャンバー内温度: 298 K / 装置: FEI VITROBOT MARK IV |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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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 / 実像数: 3345 / 平均露光時間: 8.0 sec. / 平均電子線量: 47.84 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
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 FIELD / Cs: 2.7 mm / 最大 デフォーカス(公称値): 2.5 µm / 最小 デフォーカス(公称値): 0.8 µm / 倍率(公称値): 48077 |
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 |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |