+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7oug | |||||||||||||||
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タイトル | STLV-1 intasome:B56 in complex with the strand-transfer inhibitor raltegravir | |||||||||||||||
要素 |
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キーワード | VIRAL PROTEIN / STLV-intasome / HTLV / integrase strand-transfer inhibitor / raltegravir. | |||||||||||||||
機能・相同性 | 機能・相同性情報 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 / Platelet sensitization by LDL / CTLA4 inhibitory signaling / 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 / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / Resolution of Sister Chromatid Cohesion / nuclear periphery / RHO GTPases Activate Formins / RAF activation / Degradation of beta-catenin by the destruction complex / euchromatin / DNA integration / RNA stem-loop binding / Negative regulation of MAPK pathway / RNA-directed DNA polymerase activity / Separation of Sister Chromatids / RNA-DNA hybrid ribonuclease activity / Regulation of TP53 Degradation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / response to heat / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / DNA recombination / 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 | Simian T-lymphotropic virus 1 (ウイルス) Homo sapiens (ヒト) | |||||||||||||||
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: 3.1 Å | |||||||||||||||
データ登録者 | Barski, M.S. / Ballandras-Colas, A. / Cronin, N.B. / Pye, V.E. / Cherepanov, P. / Maertens, G.N. | |||||||||||||||
資金援助 | 英国, 米国, 4件
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引用 | ジャーナル: Nat Commun / 年: 2021 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 |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7oug.cif.gz | 363.1 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7oug.ent.gz | 275.9 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7oug.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 7oug_validation.pdf.gz | 1.2 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7oug_full_validation.pdf.gz | 1.2 MB | 表示 | |
XML形式データ | 7oug_validation.xml.gz | 60.5 KB | 表示 | |
CIF形式データ | 7oug_validation.cif.gz | 90.8 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/ou/7oug ftp://data.pdbj.org/pub/pdb/validation_reports/ou/7oug | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-タンパク質 , 2種, 6分子 DEABFC
#1: タンパク質 | 分子量: 33943.539 Da / 分子数: 4 / 変異: A219E / 由来タイプ: 組換発現 由来: (組換発現) Simian T-lymphotropic virus 1 (ウイルス) 遺伝子: pol / 発現宿主: Escherichia coli (大腸菌) / Variant (発現宿主): DE3 pLacI (Rosetta-2) / 参照: UniProt: Q4QY51 #2: タンパク質 | 分子量: 80394.680 Da / 分子数: 2 / 由来タイプ: 組換発現 詳細: fusion construct containing human LEDGF (residues 1-324 thus without the IBD domain) (gene PSIP1; O75475)) and human B56gammma (residues 11-380) regulatory subunit of PP2A (gene PPP2R5C) (no ...詳細: fusion construct containing human LEDGF (residues 1-324 thus without the IBD domain) (gene PSIP1; O75475)) and human B56gammma (residues 11-380) regulatory subunit of PP2A (gene PPP2R5C) (no space for these details below).,fusion construct containing human LEDGF (residues 1-324 thus without the IBD domain) (gene PSIP1; O75475)) and human B56gammma (residues 11-380) regulatory subunit of PP2A (gene PPP2R5C) (no space for these details below). 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: PPP2R5C, KIAA0044 / 発現宿主: Escherichia coli (大腸菌) / Variant (発現宿主): LOBSTR(RIL) / 参照: UniProt: O75475, UniProt: Q13362 |
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-DNA鎖 , 2種, 4分子 IKJL
#3: DNA鎖 | 分子量: 9221.909 Da / 分子数: 2 / 由来タイプ: 合成 由来: (合成) Simian T-lymphotropic virus 1 (ウイルス) #4: DNA鎖 | 分子量: 8593.560 Da / 分子数: 2 / 由来タイプ: 合成 由来: (合成) Simian T-lymphotropic virus 1 (ウイルス) |
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-非ポリマー , 4種, 18分子
#5: 化合物 | ChemComp-ZN / #6: 化合物 | ChemComp-MG / #7: 化合物 | #8: 水 | ChemComp-HOH / | |
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-詳細
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 |
-試料調製
構成要素 | 名称: Complex of STLV-1 MarB43 integrase with nascent viral DNA, the human PP2A B56 subunit and the inhibitor raltegravir タイプ: COMPLEX 詳細: Sample composition and source have been described in "macromolecules" Entity ID: #1-#4 / 由来: MULTIPLE SOURCES | |||||||||||||||
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分子量 | 値: 0.3311 MDa / 実験値: NO | |||||||||||||||
緩衝液 | pH: 6 | |||||||||||||||
緩衝液成分 |
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試料 | 濃度: 0.76 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: Complex was isolated by size exclusion chromatography | |||||||||||||||
試料支持 | 詳細: 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. グリッドの材料: GOLD / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: UltrAuFoil R1.2/1.3 | |||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 95 % / 凍結前の試料温度: 295.15 K |
-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: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 50 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
電子光学装置 | 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 |
-解析
ソフトウェア | 名称: PHENIX / バージョン: dev_4155: / 分類: 精密化 | ||||||||||||||||||||||||||||||||||||||||||||
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 2840121 | ||||||||||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C2 (2回回転対称) | ||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.1 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 111051 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: RIGID BODY FIT 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. | ||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 6Z2Y 6z2y Accession code: 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. Source name: PDB / タイプ: experimental model | ||||||||||||||||||||||||||||||||||||||||||||
拘束条件 |
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