7T17

Zika Virus asymmetric unit bound with IgM antibody DH1017 Fab fragment

Summary for 7T17

• Entry DOI: 10.2210/pdb7t17/pdb
• EMDB information: 25606
• Descriptor: DH1017.IgM FabC constant domain, DH1017.IgM LambdaC constant domain, DH1017.IgM IgH, ... (5 entities in total)
• Functional Keywords: zika virus particle, igm, fab fragment, neutralization, virus
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 199678.72

Authors

Miller, A.S.,Kuhn, R.J. (deposition date: 2021-12-01, release date: 2022-11-23, Last modification date: 2024-06-05)

Primary citation

Singh, T.,Hwang, K.K.,Miller, A.S.,Jones, R.L.,Lopez, C.A.,Dulson, S.J.,Giuberti, C.,Gladden, M.A.,Miller, I.,Webster, H.S.,Eudailey, J.A.,Luo, K.,Von Holle, T.,Edwards, R.J.,Valencia, S.,Burgomaster, K.E.,Zhang, S.,Mangold, J.F.,Tu, J.J.,Dennis, M.,Alam, S.M.,Premkumar, L.,Dietze, R.,Pierson, T.C.,Ooi, E.E.,Lazear, H.M.,Kuhn, R.J.,Permar, S.R.,Bonsignori, M.
A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization.
Cell, 185:4826-4840.e17, 2022

PubMed Abstract: Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.

PubMed: 36402135
DOI: 10.1016/j.cell.2022.10.023

Experimental method

ELECTRON MICROSCOPY (5.26 Å)