7LZE

Cryo-EM Structure of disulfide stabilized HMPV F v4-B

Summary for 7LZE

• Entry DOI: 10.2210/pdb7lze/pdb
• EMDB information: 23605
• Descriptor: Fusion glycoprotein F0, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: hmpv f, postfusion, prefusion, viral protein, immunization
• Biological source: Human metapneumovirus
• Total number of polymer chains: 3
• Total formula weight: 165358.36

Authors

Gorman, J.,Kwong, P.D. (deposition date: 2021-03-09, release date: 2021-08-25, Last modification date: 2024-11-20)

Primary citation

Stewart-Jones, G.B.E.,Gorman, J.,Ou, L.,Zhang, B.,Joyce, M.G.,Yang, L.,Cheng, C.,Chuang, G.Y.,Foulds, K.E.,Kong, W.P.,Olia, A.S.,Sastry, M.,Shen, C.H.,Todd, J.P.,Tsybovsky, Y.,Verardi, R.,Yang, Y.,Collins, P.L.,Corti, D.,Lanzavecchia, A.,Scorpio, D.G.,Mascola, J.R.,Buchholz, U.J.,Kwong, P.D.
Interprotomer disulfide-stabilized variants of the human metapneumovirus fusion glycoprotein induce high titer-neutralizing responses.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Human metapneumovirus (HMPV) is a major cause of respiratory disease worldwide, particularly among children and the elderly. Although there is no licensed HMPV vaccine, promising candidates have been identified for related pneumoviruses based on the structure-based stabilization of the fusion (F) glycoprotein trimer, with prefusion-stabilized F glycoprotein trimers eliciting significantly higher neutralizing responses than their postfusion F counterparts. However, immunization with HMPV F trimers in either prefusion or postfusion conformations has been reported to elicit equivalent neutralization responses. Here we investigate the impact of stabilizing disulfides, especially interprotomer disulfides (IP-DSs) linking protomers of the F trimer, on the elicitation of HMPV-neutralizing responses. We designed F trimer disulfides, screened for their expression, and used electron microscopy (EM) to confirm their formation, including that of an unexpected postfusion variant. In mice, IP-DS-stabilized prefusion and postfusion HMPV F elicited significantly higher neutralizing responses than non-IP-DS-stabilized HMPV Fs. In macaques, the impact of IP-DS stabilization was more measured, although IP-DS-stabilized variants of either prefusion or postfusion HMPV F induced neutralizing responses many times the average titers observed in a healthy human cohort. Serological and absorption-based analyses of macaque responses revealed elicited HMPV-neutralizing responses to be absorbed differently by IP-DS-containing and by non-IP-DS-containing postfusion Fs, suggesting IP-DS stabilization to alter not only the immunogenicity of select epitopes but their antigenicity as well. We speculate the observed increase in immunogenicity by IP-DS trimers to be related to reduced interprotomer flexibility within the HMPV F trimer.

PubMed: 34551978
DOI: 10.1073/pnas.2106196118

Experimental method

ELECTRON MICROSCOPY (3.23 Å)