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Structure paper

TitleStructural basis for the synergistic neutralization of coxsackievirus B1 by a triple-antibody cocktail.
Journal, issue, pagesCell Host Microbe, Vol. 30, Issue 9, Page 1279-11294.e6, Year 2022
Publish dateSep 14, 2022
AuthorsQingbing Zheng / Rui Zhu / Zhichao Yin / Longfa Xu / Hui Sun / Hai Yu / Yuanyuan Wu / Yichao Jiang / Qiongzi Huang / Yang Huang / Dongqing Zhang / Liqin Liu / Hongwei Yang / Maozhou He / Zhenhong Zhou / Yanan Jiang / Zhenqin Chen / Huan Zhao / Yuqiong Que / Zhibo Kong / Lizhi Zhou / Tingting Li / Jun Zhang / Wenxin Luo / Ying Gu / Tong Cheng / Shaowei Li / Ningshao Xia /
PubMed AbstractCoxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. ...Coxsackievirus B1 (CVB1) is an emerging pathogen associated with severe neonatal diseases including aseptic meningitis, myocarditis, and pancreatitis and also with the development of type 1 diabetes. We characterize the binding and therapeutic efficacies of three CVB1-specific neutralizing antibodies (nAbs) identified for their ability to inhibit host receptor engagement. High-resolution cryo-EM structures showed that these antibodies recognize different epitopes but with an overlapping region in the capsid VP2 protein and specifically the highly variable EF loop. Moreover, they perturb capsid-receptor interactions by binding various viral particle forms. Antibody combinations achieve synergetic neutralization via a stepwise capsid transition and virion disruption, indicating dynamic changes in the virion in response to multiple nAbs targeting the receptor-binding site. Furthermore, this three-antibody cocktail protects against lethal challenge in neonatal mice and limits pancreatitis and viral replication in a non-obese diabetic mouse model. These results illustrate the utility of nAbs for rational design of therapeutics against picornaviruses such as CVB.
External linksCell Host Microbe / PubMed:36002016
MethodsEM (single particle)
Resolution3.02 - 4.18 Å
Structure data

EMDB-32967, PDB-7x2g:
Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb nAb 2E6 (CVB1-E:2E6)
Method: EM (single particle) / Resolution: 3.58 Å

EMDB-32968, PDB-7x2i:
Cryo-EM structure of Coxsackievirus B1 pre-A particle in complex with nAb 2E6 (CVB1-pre-A:2E6)
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-32969, PDB-7x2o:
Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 2E6 (CVB1-M:2E6)
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-32970, PDB-7x2t:
Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (CVB1-M:8A10)
Method: EM (single particle) / Resolution: 3.69 Å

EMDB-32973, PDB-7x2w:
Cryo-EM structure of Coxsackievirus B1 pre-A particle in complex with nAb 8A10 (CVB1-pre-A:8A10)
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-32980, PDB-7x37:
Cryo-EM structure of Coxsackievirus B1 A particle in complex with nAb 2E6 (CVB1-A:2E6)
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-32981, PDB-7x38:
Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 8A10 (CVB1-E:8A10)
Method: EM (single particle) / Resolution: 3.52 Å

EMDB-32983, PDB-7x3c:
Cryo-EM structure of Coxsackievirus B1 muture virion in complex with nAbs 8A10 and 5F5 (CVB1-M:8A10:5F5)
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-32984, PDB-7x3d:
Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 9A3 (CVB1-M:9A3)
Method: EM (single particle) / Resolution: 3.48 Å

EMDB-32985, PDB-7x3e:
Cryo-EM structure of Coxsackievirus B1 pre-A-particle in complex with nAb 9A3 (CVB1-pre-A:9A3)
Method: EM (single particle) / Resolution: 3.44 Å

EMDB-32986, PDB-7x3f:
Cryo-EM structure of Coxsackievirus B1 A-particle in complex with nAb 9A3 (CVB1-A:9A3)
Method: EM (single particle) / Resolution: 3.52 Å

EMDB-32998, PDB-7x40:
Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10 and 2E6)
Method: EM (single particle) / Resolution: 3.02 Å

EMDB-32999, PDB-7x42:
Cryo-EM structure of Coxsackievirus B1 pre-A-particle in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10 and 2E6)
Method: EM (single particle) / Resolution: 3.88 Å

EMDB-33000, PDB-7x46:
Cryo-EM structure of Coxsackievirus B1 A-particle in complex with nAb 2E6 (classified from CVB1 mature virion in complex with 8A10 and 2E6)
Method: EM (single particle) / Resolution: 3.85 Å

EMDB-33001, PDB-7x47:
Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 2E6 (classified from CVB1 mature virion in complex with 8A10 and 2E6)
Method: EM (single particle) / Resolution: 3.66 Å

EMDB-33002, PDB-7x49:
Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10 and 9A3)
Method: EM (single particle) / Resolution: 3.13 Å

EMDB-33003: Cryo-EM structure of Coxsackievirus B1 A-particle in complex with nAb 9A3 (classified from CVB1 mature virion in complex with 8A10 and 9A3)
Method: EM (single particle) / Resolution: 4.01 Å

EMDB-33004, PDB-7x4k:
Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 9A3 (classified from CVB1 mature virion in complex with 8A10 and 9A3)
Method: EM (single particle) / Resolution: 3.82 Å

EMDB-33005, PDB-7x4m:
Cryo-EM structure of Coxsackievirus B1 mature virion in complex with nAb 8A10 (classified from CVB1 mature virion in complex with 8A10, 2E6 and 9A3)
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-33006: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 2E6 (classified from CVB1 mature virion in complex with 8A10, 2E6 and 9A3)
Method: EM (single particle) / Resolution: 4.18 Å

Chemicals

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

Source
  • Severe acute respiratory syndrome coronavirus 2
  • mus musculus (house mouse)
  • coxsackievirus b1
KeywordsVIRUS / Coxsackievirus B1 / Neutralizing antiboy / Cryo-EM / Neutralizing antibody

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