+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 6opo | ||||||||||||
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タイトル | Symmetric model of CD4- and 17-bound B41 HIV-1 Env SOSIP in complex with DDM | ||||||||||||
要素 |
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キーワード | VIRAL PROTEIN/Immune System (ウイルス性) / HIV-1 / Env / CD4 / receptor-bound state / detergent (洗剤) / DDM / VIRAL PROTEIN (ウイルスタンパク質) / VIRAL PROTEIN-Immune System complex (ウイルス性) | ||||||||||||
機能・相同性 | 機能・相同性情報 helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / maintenance of protein location in cell / T cell selection / MHC class II protein binding / cellular response to granulocyte macrophage colony-stimulating factor stimulus / interleukin-15-mediated signaling pathway / positive regulation of monocyte differentiation / Nef Mediated CD4 Down-regulation ...helper T cell enhancement of adaptive immune response / interleukin-16 binding / interleukin-16 receptor activity / maintenance of protein location in cell / T cell selection / MHC class II protein binding / cellular response to granulocyte macrophage colony-stimulating factor stimulus / interleukin-15-mediated signaling pathway / positive regulation of monocyte differentiation / Nef Mediated CD4 Down-regulation / Alpha-defensins / positive regulation of kinase activity / regulation of T cell activation / extracellular matrix structural constituent / T cell receptor complex / Other interleukin signaling / enzyme-linked receptor protein signaling pathway / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / regulation of calcium ion transport / macrophage differentiation / Generation of second messenger molecules / T cell differentiation / PD-1 signaling / positive regulation of protein kinase activity / Binding and entry of HIV virion / coreceptor activity / positive regulation of calcium-mediated signaling / positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / T細胞 / positive regulation of interleukin-2 production / protein tyrosine kinase binding / host cell endosome membrane / Vpu mediated degradation of CD4 / calcium-mediated signaling / cell surface receptor protein tyrosine kinase signaling pathway / clathrin-coated endocytic vesicle membrane / transmembrane signaling receptor activity / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of T cell activation / Cargo recognition for clathrin-mediated endocytosis / Downstream TCR signaling / virus receptor activity / MHC class II protein complex binding / Clathrin-mediated endocytosis / signaling receptor activity / clathrin-dependent endocytosis of virus by host cell / positive regulation of canonical NF-kappaB signal transduction / 獲得免疫系 / defense response to Gram-negative bacterium / positive regulation of MAPK cascade / positive regulation of viral entry into host cell / エンドソーム / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / viral protein processing / 細胞接着 / 免疫応答 / 脂質ラフト / positive regulation of protein phosphorylation / fusion of virus membrane with host plasma membrane / external side of plasma membrane / virus-mediated perturbation of host defense response / 小胞体 / fusion of virus membrane with host endosome membrane / エンベロープ (ウイルス) / lipid binding / endoplasmic reticulum membrane / virion attachment to host cell / protein kinase binding / host cell plasma membrane / virion membrane / structural molecule activity / positive regulation of DNA-templated transcription / enzyme binding / シグナル伝達 / protein homodimerization activity / zinc ion binding / identical protein binding / 細胞膜 類似検索 - 分子機能 | ||||||||||||
生物種 | Human immunodeficiency virus 1 (ヒト免疫不全ウイルス) 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: 3.5 Å | ||||||||||||
データ登録者 | Ozorowski, G. / Torres, J.L. / Ward, A.B. | ||||||||||||
資金援助 | 米国, 3件
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引用 | ジャーナル: Cell Rep / 年: 2020 タイトル: A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket near the Fusion Peptide. 著者: Gabriel Ozorowski / Jonathan L Torres / Diogo Santos-Martins / Stefano Forli / Andrew B Ward / 要旨: Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron ...Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. Here, while studying the receptor-bound envelope glycoprotein conformation by cryoelectron microscopy (cryo-EM), we identify a pocket near the base of the trimer containing a bound detergent molecule and perform in silico drug screening by using a library of drug-like and commercially available molecules. After down-selection, we solve cryo-EM structures that validate the binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrates low micromolar inhibition of the autologous virus by using a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing an additional target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains. #1: ジャーナル: Biorxiv / 年: 2020 タイトル: A strain-specific inhibitor of receptor-bound HIV-1 targets a pocket near the fusion peptide and offers a template for drug design 著者: Ozorowski, G. / Torres, J.L. / Santos-Martins, D. / Forli, S. / Ward, A.B. | ||||||||||||
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 | 6opo.cif.gz | 557.7 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb6opo.ent.gz | 456.6 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 6opo.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
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/op/6opo ftp://data.pdbj.org/pub/pdb/validation_reports/op/6opo | HTTPS FTP |
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-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
-Envelope glycoprotein ... , 2種, 6分子 ADJBFM
#1: タンパク質 | 分子量: 58872.902 Da / 分子数: 3 / 由来タイプ: 組換発現 由来: (組換発現) Human immunodeficiency virus 1 (ヒト免疫不全ウイルス) 遺伝子: env / 細胞株 (発現宿主): HEK293F / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: B3UES2 #3: タンパク質 | 分子量: 17357.824 Da / 分子数: 3 / 由来タイプ: 組換発現 由来: (組換発現) Human immunodeficiency virus 1 (ヒト免疫不全ウイルス) 株: B41 / 遺伝子: env / 細胞株 (発現宿主): HEK293F / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: B3UEZ6 |
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-タンパク質 , 1種, 3分子 CGN
#4: タンパク質 | 分子量: 23039.172 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: CD4 / 細胞株 (発現宿主): HEK293F / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P01730 |
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-抗体 , 2種, 6分子 LEKHIO
#2: 抗体 | 分子量: 23425.869 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 細胞株 (発現宿主): HEK293F / 発現宿主: Homo sapiens (ヒト) #5: 抗体 | 分子量: 24484.455 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 細胞株 (発現宿主): HEK293F / 発現宿主: Homo sapiens (ヒト) |
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-糖 , 5種, 51分子
#6: 多糖 | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose #7: 多糖 | #8: 多糖 | #9: 糖 | ChemComp-NAG / #10: 糖 | |
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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: HIV-1 Env B41 SOSIP in complex with soluble CD4, 17b Fab and DDM タイプ: COMPLEX / Entity ID: #1-#5 / 由来: MULTIPLE SOURCES | ||||||||||||||||
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分子量 | 値: 0.63 MDa / 実験値: NO | ||||||||||||||||
由来(天然) | 生物種: Human immunodeficiency virus 1 (ヒト免疫不全ウイルス) | ||||||||||||||||
由来(組換発現) | 生物種: Homo sapiens (ヒト) | ||||||||||||||||
緩衝液 | pH: 7.4 / 詳細: DDM added shortly (<5 minutes) prior to freezing. | ||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||
試料支持 | グリッドの材料: COPPER / グリッドのタイプ: C-flat-2/2 4C | ||||||||||||||||
急速凍結 | 装置: HOMEMADE PLUNGER / 凍結剤: ETHANE |
-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 FIELDBright-field microscopy / 倍率(公称値): 22500 X / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 1000 nm / Cs: 2.7 mm / C2レンズ絞り径: 70 µm / アライメント法: COMA FREE |
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 | 平均露光時間: 10 sec. / 電子線照射量: 58 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 実像数: 1148 |
画像スキャン | サンプリングサイズ: 5 µm / 動画フレーム数/画像: 50 |
-解析
EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C3 (3回回転対称) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.5 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 183480 詳細: Resolution estimated by convergence between CryoSparc2 loose mask value, and by applying the same CryoSparc2 mask and half maps in Relion PostProcess. クラス平均像の数: 3 / 対称性のタイプ: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 5VN3 |