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

Summary for 8VYN

• Entry DOI: 10.2210/pdb8vyn/pdb
• Related: 8VYM
• EMDB information: 43667 43670 43672
• Descriptor: Envelope glycoprotein B, 7H3 Fab Heavy Chain, 7H3 Fab Light Chain, ... (8 entities in total)
• Functional Keywords: orthoherpesvirus, betaherpesvirus, cytomegalovirus, human betaherpesvirus 5, human cytomegalovirus, hcmv, glycoprotein b, gb, hcmv gb, prefusion, prefusion-stabilized, disulfide, viral protein, 7h2, 1g2, viral protein-immune system complex, viral protein/immune system
• Biological source: Human betaherpesvirus 5; More
• Total number of polymer chains: 15
• Total formula weight: 558988.45

Authors

Sponholtz, M.R.,Byrne, P.O.,McLellan, J.S. (deposition date: 2024-02-09, release date: 2024-09-18, Last modification date: 2025-05-21)

Primary citation

Sponholtz, M.R.,Byrne, P.O.,Lee, A.G.,Ramamohan, A.R.,Goldsmith, J.A.,McCool, R.S.,Zhou, L.,Johnson, N.V.,Hsieh, C.L.,Connors, M.,Karthigeyan, K.P.,Crooks, C.M.,Fuller, A.S.,Campbell, J.D.,Permar, S.R.,Maynard, J.A.,Yu, D.,Bottomley, M.J.,McLellan, J.S.
Structure-based design of a soluble human cytomegalovirus glycoprotein B antigen stabilized in a prefusion-like conformation.
Proc.Natl.Acad.Sci.USA, 121:e2404250121-e2404250121, 2024

PubMed Abstract: Human 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 Å 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.

PubMed: 39231203
DOI: 10.1073/pnas.2404250121

Experimental method

ELECTRON MICROSCOPY (2.8 Å)