7ssc
TRL345 lineage ancestor I8 Fab bound to an HCMV gB-derived peptide
Structural highlights
FunctionGB_HCMVA Envelope glycoprotein that plays a role in host cell entry, cell to-cell virus transmission, and fusion of infected cells. May be involved in the initial attachment via binding to heparan sulfate together with the gM/gN complex that binds heparin with higher affinity. Interacts with host integrin ITGB1, PDGFRA and EGFR that likely serve as postattachment entry receptors. Participates also in the fusion of viral and cellular membranes leading to virus entry into the host cell. Membrane fusion is mediated by the fusion machinery composed at least of gB and the heterodimer gH/gL.[1] [2] Viral ligand for CD209/DC-SIGN. This interaction allows capture of viral particles by dendritic (DCs) cells and subsequent virus transmission to permissive cells. DCs are professional antigen presenting cells, critical for host immunity by inducing specific immune responses against a broad variety of pathogens. They act as sentinels in various tissues where they entrap pathogens and convey them to local lymphoid tissue or lymph node for establishment of immunity. CMV subverts the migration properties of dendritic cells to gain access to target organs or susceptible cells (By similarity). Publication Abstract from PubMedCytomegalovirus (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. A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus.,Jenks JA, Amin S, Sponholtz MR, Kumar A, Wrapp D, Venkatayogi S, Tu JJ, Karthigeyan K, Valencia SM, Connors M, Harnois MJ, Hora B, Rochat E, McLellan JS, Wiehe K, Permar SR PLoS Pathog. 2023 Jan 20;19(1):e1011107. doi: 10.1371/journal.ppat.1011107. , eCollection 2023 Jan. PMID:36662906[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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