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基本情報
登録情報 | データベース: EMDB / ID: EMD-13075 | |||||||||||||||
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タイトル | Structure of the STLV intasome:B56 complex bound to the strand-transfer inhibitor XZ450 | |||||||||||||||
![]() | DeepEMenhancer highest target map | |||||||||||||||
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機能・相同性 | ![]() protein phosphatase type 2A complex / protein phosphatase regulator activity / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated ...protein phosphatase type 2A complex / protein phosphatase regulator activity / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / supercoiled DNA binding / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / CTLA4 inhibitory signaling / Platelet sensitization by LDL / 2-LTR circle formation / Formation of WDR5-containing histone-modifying complexes / Vpr-mediated nuclear import of PICs / protein phosphatase activator activity / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / mRNA 5'-splice site recognition / chromosome, centromeric region / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / heterochromatin / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Resolution of Sister Chromatid Cohesion / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / nuclear periphery / RHO GTPases Activate Formins / RAF activation / euchromatin / Degradation of beta-catenin by the destruction complex / DNA integration / Negative regulation of MAPK pathway / RNA stem-loop binding / Separation of Sister Chromatids / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Regulation of TP53 Degradation / response to heat / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA recombination / DNA-binding transcription factor binding / response to oxidative stress / transcription coactivator activity / chromatin remodeling / negative regulation of cell population proliferation / chromatin binding / Golgi apparatus / signal transduction / positive regulation of transcription by RNA polymerase II / RNA binding / zinc ion binding / nucleoplasm / nucleus / cytosol 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: 3.0 Å | |||||||||||||||
![]() | Barski MS / Ballandras-Colas A / Cronin NB / Pye VE / Cherepanov P / Maertens GN | |||||||||||||||
資金援助 | ![]() ![]()
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![]() | ![]() タイトル: Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures. 著者: Michal S Barski / Teresa Vanzo / Xue Zhi Zhao / Steven J Smith / Allison Ballandras-Colas / Nora B Cronin / Valerie E Pye / Stephen H Hughes / Terrence R Burke / Peter Cherepanov / Goedele N Maertens / ![]() ![]() ![]() ![]() 要旨: Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this ...Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection. | |||||||||||||||
履歴 |
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構造の表示
ムービー |
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構造ビューア | EMマップ: ![]() ![]() ![]() |
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 | ![]() | 92.5 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 25.8 KB 25.8 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 10.8 KB | 表示 | ![]() |
画像 | ![]() | 143.4 KB | ||
その他 | ![]() ![]() ![]() | 5.5 MB 82.8 MB 82.8 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-検証レポート
文書・要旨 | ![]() | 427.3 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 426.8 KB | 表示 | |
XML形式データ | ![]() | 17.7 KB | 表示 | |
CIF形式データ | ![]() | 22.8 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
EMDBのページ | ![]() ![]() |
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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 | DeepEMenhancer highest target map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.1 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
-追加マップ: denmod map which was used for model real space refinement
ファイル | emd_13075_additional_1.map | ||||||||||||
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注釈 | denmod map which was used for model real space refinement | ||||||||||||
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
ファイル | emd_13075_half_map_1.map | ||||||||||||
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注釈 | half map 1 | ||||||||||||
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
ファイル | emd_13075_half_map_2.map | ||||||||||||
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注釈 | half map 2 | ||||||||||||
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 : Complex of STLV-1 MarB43 integrase with nascent viral DNA, the hu...
全体 | 名称: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the drug inhibitor XZ450 |
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要素 |
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-超分子 #1: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the hu...
超分子 | 名称: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the drug inhibitor XZ450 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#4 詳細: Sample composition and source have been described in "macromolecules" |
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分子量 | 理論値: 331.1 KDa |
-分子 #1: Integrase
分子 | 名称: Integrase / タイプ: protein_or_peptide / ID: 1 / コピー数: 4 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 33.943539 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: GPEFQLSPAK LHSFTHCGQA ALTLHGATTT EALNILHSCH ACRKNNPQHQ MPRGHIRRGL LPNHIWQGDI THFKYKNTLY RLHVWVDTF SGSVSATHKK RETSSEAISS LLHAIAHLGR PSHINTDNGP AYASQEFQHA CTSLAIRHTT HIPYNPTSSG L VERTNGIL ...文字列: GPEFQLSPAK LHSFTHCGQA ALTLHGATTT EALNILHSCH ACRKNNPQHQ MPRGHIRRGL LPNHIWQGDI THFKYKNTLY RLHVWVDTF SGSVSATHKK RETSSEAISS LLHAIAHLGR PSHINTDNGP AYASQEFQHA CTSLAIRHTT HIPYNPTSSG L VERTNGIL KTLLYKYFSD NPNLPMDNAL SVALWTINHL NVLTHCQKTR WQLHHSPRLP PIPEEKPVTT SKTHWYYFKI PG LNSRQWK GPQRALQEAA GAALIPVSDT AAQWIPWKLL KRAVCPRLAG DTADPKERDH QHHG |
-分子 #2: Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-1 of...
分子 | 名称: Isoform 3 of PC4 and SFRS1-interacting protein,Isoform Gamma-1 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform タイプ: protein_or_peptide / ID: 2 / コピー数: 2 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 80.39468 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: SMTRDFKPGD LIFAKMKGYP HWPARVDEVP DGAVKPPTNK LPIFFFGTHE TAFLGPKDIF PYSENKEKYG KPNKRKGFNE GLWEIDNNP KVKFSSQQAA TKQSNASSDV EVEEKETSVS KEDTDHEEKA SNEDVTKAVD ITTPKAARRG RKRKAEKQVE T EEAGVVTT ...文字列: SMTRDFKPGD LIFAKMKGYP HWPARVDEVP DGAVKPPTNK LPIFFFGTHE TAFLGPKDIF PYSENKEKYG KPNKRKGFNE GLWEIDNNP KVKFSSQQAA TKQSNASSDV EVEEKETSVS KEDTDHEEKA SNEDVTKAVD ITTPKAARRG RKRKAEKQVE T EEAGVVTT ATASVNLKVS PKRGRPAATE VKIPKPRGRP KMVKQPCPSE SDIITEEDKS KKKGQEEKQP KKQPKKDEEG QK EEDKPRK EPDKKEGKKE VESKRKNLAK TGVTSTSDSE EEGDDQEGEK KRKGGRNFQT AHRRNMLKGQ HEKEAADRKR KQE EQMETE FMVVDAANSN GPFQPVVLLH IRDVPPADQE KLFIQKLRQC CVLFDFVSDP LSDLKWKEVK RAALSEMVEY ITHN RNVIT EPIYPEVVHM FAVNMFRTLP PSSNPTGAEF DPEEDEPTLE AAWPHLQLVY EFFLRFLESP DFQPNIAKKY IDQKF VLQL LELFDSEDPR ERDFLKTTLH RIYGKFLGLR AYIRKQINNI FYRFIYETEH HNGIAELLEI LGSIINGFAL PLKEEH KIF LLKVLLPLHK VKSLSVYHPQ LAYCVVQFLE KDSTLTEPVV MALLKYWPKT HSPKEVMFLN ELEEILDVIE PSEFVKI ME PLFRQLAKCV SSPHFQVAER ALYYWNNEYI MSLISDNAAK ILPIMFPSLY RNSKT |
-分子 #3: DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*...
分子 | 名称: DNA (5'-D(*AP*CP*TP*GP*TP*GP*TP*TP*TP*GP*GP*CP*GP*CP*TP*TP*CP*TP*CP*TP*C)-3') タイプ: dna / ID: 3 / コピー数: 2 / 分類: DNA |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 9.221909 KDa |
配列 | 文字列: (DA)(DC)(DT)(DG)(DT)(DG)(DT)(DT)(DT)(DG) (DG)(DC)(DG)(DC)(DT)(DT)(DC)(DT)(DC)(DT) (DC)(DC)(DC)(DG)(DG)(DA)(DG)(DA)(DG) (DA) |
-分子 #4: DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*...
分子 | 名称: DNA (5'-D(*GP*AP*GP*AP*GP*AP*AP*GP*CP*GP*CP*CP*AP*AP*AP*CP*AP*CP*A)-3') タイプ: dna / ID: 4 / コピー数: 2 / 分類: DNA |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 8.59356 KDa |
配列 | 文字列: (DT)(DC)(DT)(DC)(DT)(DC)(DC)(DG)(DG)(DG) (DA)(DG)(DA)(DG)(DA)(DA)(DG)(DC)(DG)(DC) (DC)(DA)(DA)(DA)(DC)(DA)(DC)(DA) |
-分子 #5: ZINC ION
分子 | 名称: ZINC ION / タイプ: ligand / ID: 5 / コピー数: 4 / 式: ZN |
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分子量 | 理論値: 65.409 Da |
-分子 #6: MAGNESIUM ION
分子 | 名称: MAGNESIUM ION / タイプ: ligand / ID: 6 / コピー数: 4 / 式: MG |
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分子量 | 理論値: 24.305 Da |
-分子 #7: 4-azanyl-~{N}-[[2,4-bis(fluoranyl)phenyl]methyl]-6-[3-(dimethylam...
分子 | 名称: 4-azanyl-~{N}-[[2,4-bis(fluoranyl)phenyl]methyl]-6-[3-(dimethylamino)-3-oxidanylidene-propyl]-1-oxidanyl-2-oxidanylidene-1,8-naphthyridine-3-carboxamide タイプ: ligand / ID: 7 / コピー数: 2 / 式: 1L0 |
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分子量 | 理論値: 445.419 Da |
Chemical component information | ![]() ChemComp-1L0: |
-分子 #8: water
分子 | 名称: water / タイプ: ligand / ID: 8 / コピー数: 12 / 式: HOH |
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分子量 | 理論値: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-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
濃度 | 0.8 mg/mL | |||||||||
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緩衝液 | pH: 6 構成要素:
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グリッド | モデル: UltrAuFoil R1.2/1.3 / 材質: GOLD / 前処理 - タイプ: GLOW DISCHARGE 詳細: UltraAuFoil R 1.2/1.3 Au 300-mesh grids (Electron Microscopy Sciences) were glow-discharged for 4 min at 45 mA on an Emitech K100X instrument (Electron Microscopy Sciences) and covered with a ...詳細: UltraAuFoil R 1.2/1.3 Au 300-mesh grids (Electron Microscopy Sciences) were glow-discharged for 4 min at 45 mA on an Emitech K100X instrument (Electron Microscopy Sciences) and covered with a layer of graphene oxide (Sigma-Aldrich, catalogue #763705) immediately before being used. | |||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 95 % / チャンバー内温度: 295.15 K / 装置: FEI VITROBOT MARK IV | |||||||||
詳細 | Complex was isolated by size exclusion chromatography |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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特殊光学系 | エネルギーフィルター - 名称: GIF Bioquantum |
撮影 | フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 実像数: 9188 / 平均電子線量: 50.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD |
試料ステージ | ホルダー冷却材: NITROGEN |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
-原子モデル構築 1
初期モデル | PDB ID: ![]() 6z2y 詳細: 6Z2Y was fitted into the cryoEM map using Chimera. The model was adjusted to fit the map; metal ions and drug docked into the map manually using Coot. The final model was subjected to Phenix. ...詳細: 6Z2Y was fitted into the cryoEM map using Chimera. The model was adjusted to fit the map; metal ions and drug docked into the map manually using Coot. The final model was subjected to Phenix.real_space_refine using C2 NCS, secondary structure and metal ion coordination restraints. |
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精密化 | 空間: REAL / プロトコル: RIGID BODY FIT |
得られたモデル | ![]() PDB-7ouf: |