SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
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DOI：
10.1038/s41586-020-2852-1
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发表时间：
2020-12
期刊：
影响因子：
64.8
通讯作者：
Bjorkman PJ
中科院分区：
文献类型：
--
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
COVID-19大流行带来了紧迫的健康危机。靶向SARS-CoV-2刺突的宿主ACE 2受体结合域（RBD）的人中和抗体（hNAb）显示出治疗前景，并且正在临床上进行评估。为了确定SARS-CoV-2中和的结构相关性，我们解析了与SARS-CoV-2刺突三聚体或RBD复合的不同COVID-19 hNAb的8种新结构。通过结构比较，可以将其分为以下几类：（1）具有短CDRH 3的VH 3 -53 hNAb，其阻断ACE 2并仅结合“上”RBD，（2）ACE 2阻断性hNAb，其结合“上”和“下”RBD两者并可接触相邻RBD，（3）在ACE 2位点外部结合并识别“上”和“下”RBD的hNAb，和（4）先前描述的不阻断ACE 2而仅结合“向上”RBD的抗体。2类包含四种hNAb，其表位桥接RBD，包括VH 3 -53 hNAb，其使用具有疏水末端的长CDRH 3桥接相邻的“向下”RBD，从而将刺突锁定为闭合构象。表位/互补位作图显示与宿主来源的N-聚糖的相互作用很少，抗体体细胞超突变对表位接触的贡献较小。在3D中对天然存在的和体外选择的刺突突变体的亲和力测量和绘图提供了对SARS-CoV-2从感染期间引发的抗体或治疗性递送的抗体逃逸的可能性的深入了解。这些分类和结构分析提供了将当前和未来的人类RBD靶向抗体分类、评估亲合力效应、建议临床使用组合以及深入了解针对SARS-CoV-2的免疫应答的规则。
The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike show therapeutic promise and are being evaluated clincally. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to “up” RBDs, (2) ACE2-blocking hNAbs that bind both “up” and “down” RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize “up” and “down” RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only “up” RBDs. Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent “down” RBDs, thereby locking spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.
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DOI：
10.1107/s0907444910051218
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Bunkóczi G;Read RJ
通讯作者：
Read RJ
影响因子：
56.9
作者：
Hsieh, Ching-Lin;Goldsmith, Jory A.;McLellan, Jason S.
通讯作者：
McLellan, Jason S.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
DOI：
10.1107/s2059798320003198
发表时间：
2020-04-01
影响因子：
2.2
作者：
Beilsten-Edmands, James;Winter, Graeme;Evans, Gwyndaf
通讯作者：
Evans, Gwyndaf