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基本情報
登録情報 | データベース: PDB / ID: 8ydx | ||||||||||||||||||
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タイトル | Cryo-EM structure of SARS-CoV-2 spike ectodomain (HexaPro, Omicron BA.2 variant) in complex with CeSPIACE | ||||||||||||||||||
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![]() | VIRAL PROTEIN/INHIBITOR / Spike protein / VIRAL PROTEIN-INHIBITOR COMPLEX | ||||||||||||||||||
機能・相同性 | ![]() Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / viral translation / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / membrane fusion ...Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / viral translation / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / membrane fusion / entry receptor-mediated virion attachment to host cell / Attachment and Entry / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / receptor ligand activity / endocytosis involved in viral entry into host cell / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / identical protein binding / membrane / plasma membrane 類似検索 - 分子機能 | ||||||||||||||||||
生物種 | ![]() ![]() synthetic construct (人工物) | ||||||||||||||||||
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: 4.9 Å | ||||||||||||||||||
![]() | Suzuki, H. / Nakamura, S. / Fujiyoshi, Y. | ||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structure-guided engineering of a mutation-tolerant inhibitor peptide against variable SARS-CoV-2 spikes. 著者: Shun Nakamura / Yukihiro Tanimura / Risa Nomura / Hiroshi Suzuki / Kouki Nishikawa / Akiko Kamegawa / Nobutaka Numoto / Atsushi Tanaka / Shigeru Kawabata / Shoichi Sakaguchi / Akino Emi / ...著者: Shun Nakamura / Yukihiro Tanimura / Risa Nomura / Hiroshi Suzuki / Kouki Nishikawa / Akiko Kamegawa / Nobutaka Numoto / Atsushi Tanaka / Shigeru Kawabata / Shoichi Sakaguchi / Akino Emi / Youichi Suzuki / Yoshinori Fujiyoshi / ![]() 要旨: Pathogen mutations present an inevitable and challenging problem for therapeutics and the development of mutation-tolerant anti-infective drugs to strengthen global health and combat evolving ...Pathogen mutations present an inevitable and challenging problem for therapeutics and the development of mutation-tolerant anti-infective drugs to strengthen global health and combat evolving pathogens is urgently needed. While spike proteins on viral surfaces are attractive targets for preventing viral entry, they mutate frequently, making it difficult to develop effective therapeutics. Here, we used a structure-guided strategy to engineer an inhibitor peptide against the SARS-CoV-2 spike, called CeSPIACE, with mutation-tolerant and potent binding ability against all variants to enhance affinity for the invariant architecture of the receptor-binding domain (RBD). High-resolution structures of the peptide complexed with mutant RBDs revealed a mechanism of mutation-tolerant inhibition. CeSPIACE bound major mutant RBDs with picomolar affinity and inhibited infection by SARS-CoV-2 variants in VeroE6/TMPRSS2 cells (IC 4 pM to 13 nM) and demonstrated potent in vivo efficacy by inhalation administration in hamsters. Mutagenesis analyses to address mutation risks confirmed tolerance against existing and/or potential future mutations of the RBD. Our strategy of engineering mutation-tolerant inhibitors may be applicable to other infectious diseases. | ||||||||||||||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 597.8 KB | 表示 | ![]() |
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PDB形式 | ![]() | 476.3 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.6 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.6 MB | 表示 | |
XML形式データ | ![]() | 98.1 KB | 表示 | |
CIF形式データ | ![]() | 150.4 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 39184MC ![]() 8ydpC ![]() 8ydqC ![]() 8ydrC ![]() 8ydsC ![]() 8ydtC ![]() 8yduC ![]() 8ydvC ![]() 8ydwC ![]() 8ydyC ![]() 8ydzC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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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
#1: タンパク質・ペプチド | 分子量: 4721.475 Da / 分子数: 3 / 由来タイプ: 合成 / 由来: (合成) synthetic construct (人工物) #2: タンパク質 | 分子量: 144226.750 Da / 分子数: 3 / Mutation: F817P, A892P, A898P, A942P, K986P, V987P / 由来タイプ: 組換発現 詳細: the N-terminal sequence (from -18 to 12) is an mammalian secretion signal sequence, and the C-terminal sequence includes "T4 fibritin trimerization mottif" (Gly1211-Leu1237), "HRV 3C protease ...詳細: the N-terminal sequence (from -18 to 12) is an mammalian secretion signal sequence, and the C-terminal sequence includes "T4 fibritin trimerization mottif" (Gly1211-Leu1237), "HRV 3C protease cleavage site" (Leu1241-Pro1248), "8x His tag" (His1250-His1257) and "Twin-strep tag" (Trp1260-Lys1288) 由来: (組換発現) ![]() ![]() 遺伝子: S, 2 / 細胞株 (発現宿主): Expi293F / 発現宿主: ![]() #3: 糖 | ChemComp-NAG / 研究の焦点であるリガンドがあるか | N | Has protein modification | 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 |
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試料調製
構成要素 | 名称: SARS-CoV-2 spike ectodomain (HexaPro, Omicron BA.2 variant) in complex with CeSPIACE タイプ: COMPLEX / Entity ID: #1-#2 / 由来: RECOMBINANT | ||||||||||||||||
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分子量 | 実験値: NO | ||||||||||||||||
由来(天然) | 生物種: ![]() ![]() | ||||||||||||||||
由来(組換発現) | 生物種: ![]() | ||||||||||||||||
緩衝液 | pH: 8 | ||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 0.42 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: GOLD / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil 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: 278 K |
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電子顕微鏡撮影
顕微鏡 | モデル: JEOL CRYO ARM 300 |
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電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 1500 nm / Cs: 3.4 mm / C2レンズ絞り径: 50 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: JEOL 3200FSC CRYOHOLDER |
撮影 | 電子線照射量: 69.6 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) |
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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: C1 (非対称) | ||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 4.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 111423 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: RIGID BODY FIT | ||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 6XKL Accession code: 6XKL / Source name: PDB / タイプ: experimental model |