6q0s
Crystal Structure of RSV strain B18537 Prefusion-stabilized glycoprotein F Variant DS-Cav1
Structural highlights
FunctionFUS_HRSV1 During virus entry, induces fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. The fusogenic activity is inactive untill entry into host cell endosome, where a furin-like protease cleaves off a small peptide between F1 and F2. Interacts directly with heparan sulfate and may participate in virus attachment. Furthermore, the F2 subunit was identified as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells can mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.[UniProtKB:P03420] Publication Abstract from PubMedBackground: Respiratory syncytial virus (RSV) subtypes, A and B, co-circulate in annual epidemics and alternate in dominance. We have shown that a subtype A RSV fusion (F) glycoprotein, stabilized in its prefusion conformation by DS-Cav1 mutations, is a promising RSV-vaccine immunogen, capable of boosting RSV-neutralizing titers in healthy adults. In both humans and vaccine-tested animals, neutralizing titers elicited by this subtype A DS-Cav1 immunogen were ~ 2- to 3-fold higher against the homologous subtype A virus than against the heterologous subtype B virus. Methods: To understand the molecular basis for this subtype difference, we introduced DS-Cav1 mutations into RSV strain B18537 F, determined the trimeric crystal structure, and carried out immunogenicity studies. Results: The B18537 DS-Cav1 F structure at 2-A resolution afforded a precise delineation of prefusion F characteristics, including those of antigenic site O, a key trimer-apex site. Structural comparison with the subtype A prefusion F indicated 11% of surface residues to be different, with an alpha-carbon root-mean-square deviation (RMSD) of 1.2 A; antigenic site O, however, differed in 23% of its surface residues and had an alpha-carbon RMSD of 2.2 A. Immunization of vaccine-tested animals with DS-Cav1-stabilized B18537 F induced neutralizing responses ~100-fold higher than with postfusion B18537 F. Notably, elicited responses neutralized RSV subtypes A and B at similar levels and were directed towards both conserved equatorial and diverse apical regions. Conclusion: We propose that structural differences in apical and equatorial sites-coupled to differently focused immune responses-provide a molecular explanation for observed differences in elicited subtype A and B neutralizing responses. Crystal Structure and Immunogenicity of the DS-Cav1-Stabilized Fusion Glycoprotein From Respiratory Syncytial Virus Subtype B.,Joyce MG, Bao A, Chen M, Georgiev IS, Ou L, Bylund T, Druz A, Kong WP, Peng D, Rundlet EJ, Van Galen JG, Wang S, Yang Y, Zhang B, Chuang GY, McLellan JS, Graham BS, Mascola JR, Kwong PD Pathog Immun. 2019 Dec 11;4(2):294-323. doi: 10.20411/pai.v4i2.338. eCollection, 2019. PMID:31893251[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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