+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7klh | ||||||
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タイトル | SARS-CoV-2 RBD in complex with Fab 15033-7 | ||||||
要素 |
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キーワード | VIRAL PROTEIN/Immune System / SARS-CoV-2 / spike glycoprotein / Fab / VIRAL PROTEIN-Immune System complex | ||||||
機能・相同性 | 機能・相同性情報 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 / 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 | Homo sapiens (ヒト) Severe acute respiratory syndrome coronavirus 2 (ウイルス) | ||||||
手法 | X線回折 / シンクロトロン / 分子置換 / 解像度: 3 Å | ||||||
データ登録者 | Li, Z. / Rini, J.M. | ||||||
資金援助 | カナダ, 1件
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引用 | ジャーナル: J Mol Biol / 年: 2021 タイトル: Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations. 著者: Shane Miersch / Zhijie Li / Reza Saberianfar / Mart Ustav / James Brett Case / Levi Blazer / Chao Chen / Wei Ye / Alevtina Pavlenco / Maryna Gorelik / Julia Garcia Perez / Suryasree ...著者: Shane Miersch / Zhijie Li / Reza Saberianfar / Mart Ustav / James Brett Case / Levi Blazer / Chao Chen / Wei Ye / Alevtina Pavlenco / Maryna Gorelik / Julia Garcia Perez / Suryasree Subramania / Serena Singh / Lynda Ploder / Safder Ganaie / Rita E Chen / Daisy W Leung / Pier Paolo Pandolfi / Giuseppe Novelli / Giulia Matusali / Francesca Colavita / Maria R Capobianchi / Suresh Jain / J B Gupta / Gaya K Amarasinghe / Michael S Diamond / James Rini / Sachdev S Sidhu / 要旨: Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic ...Neutralizing antibodies (nAbs) hold promise as therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and tetravalent versions block entry with a potency exceeding bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug. #1: ジャーナル: bioRxiv / 年: 2020 タイトル: Tetravalent SARS-CoV-2 Neutralizing Antibodies Show Enhanced Potency and Resistance to Escape Mutations. 著者: Shane Miersch / Zhijie Li / Reza Saberianfar / Mart Ustav / James Brett Case / Levi Blazer / Chao Chen / Wei Ye / Alevtina Pavlenco / Maryna Gorelik / Julia Garcia Perez / Suryasree ...著者: Shane Miersch / Zhijie Li / Reza Saberianfar / Mart Ustav / James Brett Case / Levi Blazer / Chao Chen / Wei Ye / Alevtina Pavlenco / Maryna Gorelik / Julia Garcia Perez / Suryasree Subramania / Serena Singh / Lynda Ploder / Safder Ganaie / Rita E Chen / Daisy W Leung / Pier Paolo Pandolfi / Giuseppe Novelli / Giulia Matusali / Francesca Colavita / Maria R Capobianchi / Suresh Jain / J B Gupta / Gaya K Amarasinghe / Michael S Diamond / James Rini / Sachdev S Sidhu 要旨: Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of ...Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and its tetravalent versions can block entry with a potency that exceeds the bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, observations consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show much increased tolerance to potential virus escape mutants. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for developing potent antiviral therapies against COVID-19 and related viral threats, and our strategy can be readily applied to any antibody drug currently in development. | ||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 7klh.cif.gz | 496.3 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7klh.ent.gz | 412.7 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7klh.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 | 7klh_validation.pdf.gz | 485.4 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7klh_full_validation.pdf.gz | 492.4 KB | 表示 | |
XML形式データ | 7klh_validation.xml.gz | 42.3 KB | 表示 | |
CIF形式データ | 7klh_validation.cif.gz | 57.6 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/kl/7klh ftp://data.pdbj.org/pub/pdb/validation_reports/kl/7klh | 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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単位格子 |
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非結晶学的対称性 (NCS) | NCSドメイン:
NCSドメイン領域:
NCSアンサンブル:
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-要素
#1: 抗体 | 分子量: 23513.260 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: IgH / プラスミド: PBcmvW / 発現宿主: Homo sapiens (ヒト) / 株 (発現宿主): HEK293F #2: 抗体 | 分子量: 23366.900 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: IGK / プラスミド: PBcmvW / 発現宿主: Homo sapiens (ヒト) / 株 (発現宿主): HEK293F #3: タンパク質 | 分子量: 22631.422 Da / 分子数: 2 / 由来タイプ: 組換発現 由来: (組換発現) Severe acute respiratory syndrome coronavirus 2 (ウイルス) 遺伝子: S, 2 / プラスミド: PBtreW / 発現宿主: Homo sapiens (ヒト) / 株 (発現宿主): HEK293F GnT1-minus / 参照: UniProt: P0DTC2 #4: 糖 | 研究の焦点であるリガンドがあるか | N | |
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-実験情報
-実験
実験 | 手法: X線回折 / 使用した結晶の数: 1 |
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-試料調製
結晶 | マシュー密度: 4.26 Å3/Da / 溶媒含有率: 71.16 % |
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結晶化 | 温度: 295 K / 手法: 蒸気拡散法, ハンギングドロップ法 / pH: 7 / 詳細: 1.4 M (NH4)2SO4 16% glycerol |
-データ収集
回折 | 平均測定温度: 100 K / Serial crystal experiment: N | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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放射光源 | 由来: シンクロトロン / サイト: CLSI / ビームライン: 08B1-1 / 波長: 1.5215 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
検出器 | タイプ: DECTRIS PILATUS3 6M / 検出器: PIXEL / 日付: 2020年9月13日 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
放射 | プロトコル: SINGLE WAVELENGTH / 単色(M)・ラウエ(L): M / 散乱光タイプ: x-ray | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
放射波長 | 波長: 1.5215 Å / 相対比: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 | 解像度: 2.88→49.318 Å / Num. obs: 55200 / % possible obs: 99.9 % / 冗長度: 13.062 % / Biso Wilson estimate: 87.749 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.178 / Rrim(I) all: 0.185 / Χ2: 0.759 / Net I/σ(I): 11.18 / Num. measured all: 721045 / Scaling rejects: 92 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
反射 シェル | Diffraction-ID: 1
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-位相決定
位相決定 | 手法: 分子置換 |
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-解析
ソフトウェア |
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精密化 | 構造決定の手法: 分子置換 開始モデル: 6w41 解像度: 3→49.318 Å / SU ML: 0.49 / 交差検証法: THROUGHOUT / σ(F): 1.33 / 位相誤差: 36.09 / 立体化学のターゲット値: ML
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溶媒の処理 | 減衰半径: 0.9 Å / VDWプローブ半径: 1.11 Å / 溶媒モデル: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso max: 204.14 Å2 / Biso mean: 103.0177 Å2 / Biso min: 62.73 Å2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化ステップ | サイクル: final / 解像度: 3→49.318 Å
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Refine LS restraints NCS |
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LS精密化 シェル | Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0
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精密化 TLS | 手法: refined / Origin x: 49.2961 Å / Origin y: 28.5191 Å / Origin z: 26.7251 Å
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精密化 TLSグループ |
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