ジャーナル: Front Immunol / 年: 2022 タイトル: Nanobodies Protecting From Lethal SARS-CoV-2 Infection Target Receptor Binding Epitopes Preserved in Virus Variants Other Than Omicron. 著者: José M Casasnovas / Yago Margolles / María A Noriega / María Guzmán / Rocío Arranz / Roberto Melero / Mercedes Casanova / Juan Alberto Corbera / Nereida Jiménez-de-Oya / Pablo ...著者: José M Casasnovas / Yago Margolles / María A Noriega / María Guzmán / Rocío Arranz / Roberto Melero / Mercedes Casanova / Juan Alberto Corbera / Nereida Jiménez-de-Oya / Pablo Gastaminza / Urtzi Garaigorta / Juan Carlos Saiz / Miguel Ángel Martín-Acebes / Luis Ángel Fernández / 要旨: The emergence of SARS-CoV-2 variants that escape from immune neutralization are challenging vaccines and antibodies developed to stop the COVID-19 pandemic. Thus, it is important to establish ...The emergence of SARS-CoV-2 variants that escape from immune neutralization are challenging vaccines and antibodies developed to stop the COVID-19 pandemic. Thus, it is important to establish therapeutics directed toward multiple or specific SARS-CoV-2 variants. The envelope spike (S) glycoprotein of SARS-CoV-2 is the key target of neutralizing antibodies (Abs). We selected a panel of nine nanobodies (Nbs) from dromedary camels immunized with the receptor-binding domain (RBD) of the S, and engineered Nb fusions as humanized heavy chain Abs (hcAbs). Nbs and derived hcAbs bound with subnanomolar or picomolar affinities to the S and its RBD, and S-binding cross-competition clustered them in two different groups. Most of the hcAbs hindered RBD binding to its human ACE2 (hACE2) receptor, blocked cell entry of viruses pseudotyped with the S protein and neutralized SARS-CoV-2 infection in cell cultures. Four potent neutralizing hcAbs prevented the progression to lethal SARS-CoV-2 infection in hACE2-transgenic mice, demonstrating their therapeutic potential. Cryo-electron microscopy identified Nb binding epitopes in and out the receptor binding motif (RBM), and showed different ways to prevent virus binding to its cell entry receptor. The Nb binding modes were consistent with its recognition of SARS-CoV-2 RBD variants; mono and bispecific hcAbs efficiently bound all variants of concern except omicron, which emphasized the immune escape capacity of this latest variant.
ダウンロード / ファイル: emd_14313.map.gz / 形式: CCP4 / 大きさ: 454.3 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
ボクセルのサイズ
X=Y=Z: 0.855 Å
密度
表面レベル
登録者による: 0.025
最小 - 最大
-0.0017149223 - 1.9733533
平均 (標準偏差)
0.0008374594 (±0.021071931)
対称性
空間群: 1
詳細
EMDB XML:
マップ形状
Axis order
X
Y
Z
Origin
0
0
0
サイズ
492
492
492
Spacing
492
492
492
セル
A=B=C: 420.66 Å α=β=γ: 90.0 °
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添付データ
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試料の構成要素
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全体 : The trimeric SARS-CooV-2 spike in complex with the 2.15 neutraliz...
全体
名称: The trimeric SARS-CooV-2 spike in complex with the 2.15 neutralizing nanobody
要素
複合体: The trimeric SARS-CooV-2 spike in complex with the 2.15 neutralizing nanobody
複合体: SARS-CoV-2 spike
タンパク質・ペプチド: Spike glycoprotein
複合体: Nanobody 2.15
タンパク質・ペプチド: Camel-derived nanobody 2.15
リガンド: 2-acetamido-2-deoxy-beta-D-glucopyranose
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超分子 #1: The trimeric SARS-CooV-2 spike in complex with the 2.15 neutraliz...
超分子
名称: The trimeric SARS-CooV-2 spike in complex with the 2.15 neutralizing nanobody タイプ: complex / キメラ: Yes / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2 詳細: Complex of a soluble spike of the SARS-CoV-2 stabilized in the prefusion form with the 2.15 nanobody bound to its RBD
由来(天然)
生物種: Severe acute respiratory syndrome coronavirus 2 (ウイルス)
Rigid body refinement. Real space refinement including 5 macro cycles of:Minimization_global, local_grid search and adp. Refinement at 4.0A of resolution. Refinement included NCS.
精密化
空間: REAL / プロトコル: OTHER / 温度因子: 140 / 当てはまり具合の基準: correlation coefficient
得られたモデル
PDB-7r4i: The SARS-CoV-2 spike in complex with the 2.15 neutralizing nanobody