7SSC
TRL345 lineage ancestor I8 Fab bound to an HCMV gB-derived peptide
Summary for 7SSC
| Entry DOI | 10.2210/pdb7ssc/pdb |
| Descriptor | TRL345-I8 Fab heavy chain, TRL345-I8 Fab light chain, Envelope glycoprotein B peptide, ... (5 entities in total) |
| Functional Keywords | immunoglobulin, fusion protein, hcmv, immune system-viral protein complex, immune system/viral protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 3 |
| Total formula weight | 48760.24 |
| Authors | Sponholtz, M.R.,McLellan, J.S. (deposition date: 2021-11-10, release date: 2022-10-19, Last modification date: 2024-10-23) |
| Primary citation | Jenks, J.A.,Amin, S.,Sponholtz, M.R.,Kumar, A.,Wrapp, D.,Venkatayogi, S.,Tu, J.J.,Karthigeyan, K.,Valencia, S.M.,Connors, M.,Harnois, M.J.,Hora, B.,Rochat, E.,McLellan, J.S.,Wiehe, K.,Permar, S.R. A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus. Plos Pathog., 19:e1011107-e1011107, 2023 Cited by PubMed Abstract: Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines. PubMed: 36662906DOI: 10.1371/journal.ppat.1011107 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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