EMD-33004
Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 9A3 (classified from CVB1 mature virion in complex with 8A10 and 9A3)
EMD-33004
Single-particle3.82 Å
Deposition: 02/03/2022Map released: 28/09/2022
Last modified: 06/11/2024
Sample Organism:
Coxsackievirus B1,
Mus musculus
Sample: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 9A3 (classified from CVB1 mature virion in complex with 8A10 and 9A3)
Fitted models: 7x4k (Avg. Q-score: 0.465)
Deposition Authors: Zheng Q, Zhu R, Sun H, Cheng T, Li S, Xia N
Sample: Cryo-EM structure of Coxsackievirus B1 empty particle in complex with nAb 9A3 (classified from CVB1 mature virion in complex with 8A10 and 9A3)
Fitted models: 7x4k (Avg. Q-score: 0.465)
Deposition Authors: Zheng Q, Zhu R, Sun H, Cheng T, Li S, Xia N
Structural basis for the synergistic neutralization of coxsackievirus B1 by a triple-antibody cocktail.
Zheng Q,
Zhu R,
Yin Z 
,
Xu L,
Sun H,
Yu H,
Wu Y,
Jiang Y,
Huang Q,
Huang Y,
Zhang D,
Liu L,
Yang H,
He M,
Zhou Z,
Jiang Y,
Chen Z,
Zhao H,
Que Y,
Kong Z,
Zhou L,
Li T,
Zhang J,
Luo W,
Gu Y,
Cheng T,
Li S,
Xia N
(2022) Cell Host Microbe , 30 , 1279 - 1294.e6
,
Xu L,
Sun H,
Yu H,
Wu Y,
Jiang Y,
Huang Q,
Huang Y,
Zhang D,
Liu L,
Yang H,
He M,
Zhou Z,
Jiang Y,
Chen Z,
Zhao H,
Que Y,
Kong Z,
Zhou L,
Li T,
Zhang J,
Luo W,
Gu Y,
Cheng T,
Li S,
Xia N
(2022) Cell Host Microbe , 30 , 1279 - 1294.e6
Abstract:
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.
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.