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基本情報
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タイトル | The local refined map of Omicron spike with bispecific antibody FD01 | |||||||||
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機能・相同性 | ![]() Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell ...Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis of virus by host cell / membrane fusion / Attachment and Entry / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / symbiont-mediated suppression of host innate immune response / host cell surface receptor binding / 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 | ![]() ![]() ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.51 Å | |||||||||
![]() | Zhang X / Zhan WQ / Chen ZG / Sun L | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies. 著者: Yingdan Wang / Xiang Zhang / Yunping Ma / Yanqun Wang / Wuqiang Zhan / Qinwen Zheng / Meng Zhang / Ping Ji / Mei Liu / Qianying Liu / Tingting Sun / Tongyu Zhu / Yumei Wen / Lei Sun / Jincun ...著者: Yingdan Wang / Xiang Zhang / Yunping Ma / Yanqun Wang / Wuqiang Zhan / Qinwen Zheng / Meng Zhang / Ping Ji / Mei Liu / Qianying Liu / Tingting Sun / Tongyu Zhu / Yumei Wen / Lei Sun / Jincun Zhao / Fan Wu / Zhenguo Chen / Jinghe Huang / ![]() 要旨: The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion ...The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to most of the non-Omicron NAbs. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody GW01-16L9 (FD01) in its native full-length IgG form in complex with the Omicron S trimer revealed 5 distinct trimers and one novel trimer dimer conformation. 16L9 scFv binds the receptor-binding motif (RBM), while GW01 scFv binds a epitope outside the RBM. Two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3 RBD-up conformation, improved the affinity between IgG and the Omicron RBD, induced the formation of trimer dimer, and inhibited RBD binding to ACE2. The trimer dimer conformation might induce the aggregation of virions and contribute to the neutralization ability of FD01. These novel bispecific antibodies are strong candidates for the treatment and prevention of infection with the Omicron, BA.2, VOCs, and other sarbecoviruses. Engineering bispecific antibodies based on non-Omicron NAbs could turn the majority of NAbs into a powerful arsenal to aid the battle against the pandemic. | |||||||||
履歴 |
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構造の表示
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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 | ![]() | 111.4 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 13.1 KB 13.1 KB | 表示 表示 | ![]() |
画像 | ![]() | 27.6 KB | ||
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 | ![]() 7wopMC ![]() 7woqC ![]() 7worC ![]() 7wosC ![]() 7wouC ![]() 7wovC ![]() 7wowC M: このマップから作成された原子モデル 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
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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ボクセルのサイズ | X=Y=Z: 1.064 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
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試料の構成要素
-全体 : Omicron Spike with 16L9 and GW01
全体 | 名称: Omicron Spike with 16L9 and GW01 |
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要素 |
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-超分子 #1: Omicron Spike with 16L9 and GW01
超分子 | 名称: Omicron Spike with 16L9 and GW01 / タイプ: complex / キメラ: Yes / ID: 1 / 親要素: 0 / 含まれる分子: all |
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-超分子 #2: Omicron Spike
超分子 | 名称: Omicron Spike / タイプ: complex / キメラ: Yes / ID: 2 / 親要素: 1 / 含まれる分子: #1 |
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由来(天然) | 生物種: ![]() ![]() |
-超分子 #3: 16L9 and GW01
超分子 | 名称: 16L9 and GW01 / タイプ: complex / キメラ: Yes / ID: 3 / 親要素: 1 / 含まれる分子: #2-#3 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Spike protein S1
分子 | 名称: Spike protein S1 / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 22.523479 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: NITNLCPFDE VFNATRFASV YAWNRKRISN CVADYSVLYN LAPFFTFKCY GVSPTKLNDL CFTNVYADSF VIRGDEVRQI APGQTGNIA DYNYKLPDDF TGCVIAWNSN KLDSKVSGNY NYLYRLFRKS NLKPFERDIS TEIYQAGNKP CNGVAGFNCY F PLRSYSFR ...文字列: NITNLCPFDE VFNATRFASV YAWNRKRISN CVADYSVLYN LAPFFTFKCY GVSPTKLNDL CFTNVYADSF VIRGDEVRQI APGQTGNIA DYNYKLPDDF TGCVIAWNSN KLDSKVSGNY NYLYRLFRKS NLKPFERDIS TEIYQAGNKP CNGVAGFNCY F PLRSYSFR PTYGVGHQPY RVVVLSFELL HAPATVCGPK |
-分子 #2: 16L9
分子 | 名称: 16L9 / タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 25.730025 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: QSVLTQPPSA SGSPGQSVTI SCTGTSSDFG GYNSVSWYQQ HPGKAPKLMI YEVSKRPSGV PDRFSGSKSG NTASLTVSGL QAEDEADYY CSSYAGSNNF DVFGTGTKVT VLGGGGSGGG GSGGGGSEVQ LVESGGGLIQ PGGSLRLSCA ASGFTVSSNY M SWVRQAPG ...文字列: QSVLTQPPSA SGSPGQSVTI SCTGTSSDFG GYNSVSWYQQ HPGKAPKLMI YEVSKRPSGV PDRFSGSKSG NTASLTVSGL QAEDEADYY CSSYAGSNNF DVFGTGTKVT VLGGGGSGGG GSGGGGSEVQ LVESGGGLIQ PGGSLRLSCA ASGFTVSSNY M SWVRQAPG KGLEWVSVIY SGGSTYYADS VKGRFTISRD NSENTLYLQM NSLRAEDTAV YYCARGEIQP YYYYGMDVWG QG TTVTVSS |
-分子 #3: GW01
分子 | 名称: GW01 / タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 26.186488 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNTVNWYQQL PGTAPKLLIY SNNQRPSGVP DRFSGSKSGT SASLAISGLQ SEDEADYYC AAWDDSLNWV FGGGTKLTVL GGGGSGGGGS GGGGSEVQLV ESGGGVVQPG GSLRLSCAAS GFRFDDHAMH W VRQAPGKG ...文字列: QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNTVNWYQQL PGTAPKLLIY SNNQRPSGVP DRFSGSKSGT SASLAISGLQ SEDEADYYC AAWDDSLNWV FGGGTKLTVL GGGGSGGGGS GGGGSEVQLV ESGGGVVQPG GSLRLSCAAS GFRFDDHAMH W VRQAPGKG LEWVSVISGD GGSTYYADSV KGRFSISRDD SKNSLYLQMN SLRTEDTALY YCAKDRSYGP PDVFNYEYGM DV WGQGTTV TVSS |
-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
緩衝液 | pH: 8 |
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凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 平均電子線量: 58.0 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 / 最大 デフォーカス(公称値): 2.5 µm / 最小 デフォーカス(公称値): 1.2 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.51 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 249122 |
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初期 角度割当 | タイプ: PROJECTION MATCHING |
最終 角度割当 | タイプ: PROJECTION MATCHING |