8vyn
Soluble ectodomain of human cytomegalovirus (HCMV) glycoprotein B (gB) stabilized in a prefusion-like conformation in complex with 1G2 and 7H3, composite map (global and local) and model
Structural highlights
FunctionGB_HCMVT 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 (By similarity). 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. Publication Abstract from PubMedHuman cytomegalovirus (HCMV) glycoprotein B (gB) is a class III membrane fusion protein required for viral entry. HCMV vaccine candidates containing gB have demonstrated moderate clinical efficacy, but no HCMV vaccine has been approved. Here, we used structure-based design to identify and characterize amino acid substitutions that stabilize gB in its metastable prefusion conformation. One variant containing two engineered interprotomer disulfide bonds and two cavity-filling substitutions (gB-C7), displayed increased expression and thermostability. A 2.8 A resolution cryoelectron microscopy structure shows that gB-C7 adopts a prefusion-like conformation, revealing additional structural elements at the membrane-distal apex. Unlike previous observations for several class I viral fusion proteins, mice immunized with postfusion or prefusion-stabilized forms of soluble gB protein displayed similar neutralizing antibody titers, here specifically against an HCMV laboratory strain on fibroblasts. Collectively, these results identify initial strategies to stabilize class III viral fusion proteins and provide tools to probe gB-directed antibody responses. Structure-based design of a soluble human cytomegalovirus glycoprotein B antigen stabilized in a prefusion-like conformation.,Sponholtz MR, Byrne PO, Lee AG, Ramamohan AR, Goldsmith JA, McCool RS, Zhou L, Johnson NV, Hsieh CL, Connors M, Karthigeyan KP, Crooks CM, Fuller AS, Campbell JD, Permar SR, Maynard JA, Yu D, Bottomley MJ, McLellan JS Proc Natl Acad Sci U S A. 2024 Sep 10;121(37):e2404250121. doi: , 10.1073/pnas.2404250121. Epub 2024 Sep 4. PMID:39231203[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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