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基本情報
登録情報 | データベース: PDB / ID: 6opn | |||||||||
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タイトル | CD4- and 17-bound HIV-1 Env B41 SOSIP in complex with small molecule GO35 | |||||||||
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![]() | VIRAL PROTEIN/Immune System / HIV-1 / Env / CD4 / receptor-bound state / small molecule / fusion inhibitor / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex | |||||||||
機能・相同性 | ![]() 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 plasma membrane raft polarization / positive regulation of receptor clustering / cell surface receptor protein tyrosine kinase signaling pathway / positive regulation of establishment of T cell polarity / T cell activation / positive regulation of calcium-mediated signaling / positive regulation of interleukin-2 production / protein tyrosine kinase binding / host cell endosome membrane / clathrin-coated endocytic vesicle membrane / Vpu mediated degradation of CD4 / calcium-mediated signaling / transmembrane signaling receptor activity / Cargo recognition for clathrin-mediated endocytosis / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of T cell activation / Clathrin-mediated endocytosis / virus receptor activity / Downstream TCR signaling / MHC class II protein complex binding / signaling receptor activity / positive regulation of canonical NF-kappaB signal transduction / clathrin-dependent endocytosis of virus by host cell / defense response to Gram-negative bacterium / adaptive immune response / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / cell surface receptor signaling pathway / positive regulation of viral entry into host cell / early endosome / viral protein processing / cell adhesion / positive regulation of protein phosphorylation / membrane raft / immune response / endoplasmic reticulum lumen / external side of plasma membrane / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / lipid binding / viral envelope / endoplasmic reticulum membrane / positive regulation of DNA-templated transcription / virion attachment to host cell / protein kinase binding / apoptotic process / enzyme binding / structural molecule activity / host cell plasma membrane / virion membrane / signal transduction / protein homodimerization activity / zinc ion binding / identical protein binding / plasma membrane 類似検索 - 分子機能 | |||||||||
生物種 | ![]() ![]() ![]() | |||||||||
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 | |||||||||
![]() | Ozorowski, G. / Torres, J.L. / Ward, A.B. | |||||||||
資金援助 | ![]()
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![]() | ![]() 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: ![]() 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. | |||||||||
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構造の表示
ムービー |
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 372.9 KB | 表示 | ![]() |
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PDB形式 | ![]() | 303.2 KB | 表示 | ![]() |
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その他 | ![]() |
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-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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要素
-Envelope glycoprotein ... , 2種, 6分子 ADGBEH
#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) ![]() ![]() 遺伝子: env / 細胞株 (発現宿主): HEK293F / 発現宿主: ![]() #2: 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) ![]() ![]() 株: B41 / 遺伝子: env / 細胞株 (発現宿主): HEK293F / 発現宿主: ![]() |
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-タンパク質 / 非ポリマー , 2種, 6分子 CFI![](data/chem/img/N07.gif)
![](data/chem/img/N07.gif)
#3: 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) ![]() ![]() #7: 化合物 | |
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-糖 , 3種, 33分子 ![](data/chem/img/NAG.gif)
#4: 多糖 | #5: 多糖 | #6: 糖 | ChemComp-NAG / |
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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 |
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試料調製
構成要素 |
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分子量 |
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由来(天然) | 生物種: ![]() ![]() | |||||||||||||||||||||
由来(組換発現) | 生物種: ![]() | |||||||||||||||||||||
緩衝液 | pH: 7.4 / 詳細: Detergent (LMNG) added shortly (<5 minutes) prior to grid freezing using an 8X concentrated stock. | |||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 6 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: Complex of CD4- and 17b-bound B41 SOSIP was SEC purified and GO35 was diluted 1:100 into the complex and incubated for 1 hr prior to grid freezing. | |||||||||||||||||||||
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 400 divisions/in. / グリッドのタイプ: C-flat-2/2 | |||||||||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 283 K |
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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: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 29000 X / 最大 デフォーカス(公称値): 2200 nm / 最小 デフォーカス(公称値): 600 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: 12.5 sec. / 電子線照射量: 60 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: 1285 |
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 |
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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: 30415 詳細: FSC resolution estimation calculated using CryoSparc 2 and Relion 3.0 クラス平均像の数: 1 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: FLEXIBLE FIT / 空間: REAL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 5VN3 |