Journal Article

Transient opening of trimeric prefusion RSV F proteins

McLellan, Jason S., B. van ‘t Wout, Angélique, Gilman, Morgan S. A., Langedijk, Johannes P. M., Furmanova-Hollenstein, Polina, Pascual, Gabriel

2019

Overview

The respiratory syncytial virus (RSV) F glycoprotein is a class I fusion protein that mediates viral entry and is a major target of neutralizing antibodies. Structures of prefusion forms of RSV F, as well as other class I fusion proteins, have revealed compact trimeric arrangements, yet whether these trimeric forms can transiently open remains unknown. Here, we perform structural and biochemical studies on a recently isolated antibody, CR9501, and demonstrate that it enhances the opening of prefusion-stabilized RSV F trimers. The 3.3 Å crystal structure of monomeric RSV F bound to CR9501, combined with analysis of over 25 previously determined RSV F structures, reveals a breathing motion of the prefusion conformation. We also demonstrate that full-length RSV F trimers transiently open and dissociate on the cell surface. Collectively, these findings have implications for the function of class I fusion proteins, as well as antibody prophylaxis and vaccine development for RSV. The respiratory syncytial virus (RSV) F glycoprotein forms a trimeric complex and mediates viral entry. Using structures of RSV F in complex with antibodies, Gilman et al. here show a breathing motion of the prefusion conformation of F, resulting in transient opening of the trimeric complex in solution and on the cell surface.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 631/326/596/2116 / 631/535/1266 / 692/699/255/2514 / 9/10 / Animals / Antibodies / Antibodies, Neutralizing - chemistry / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - metabolism / Antibodies, Viral - chemistry / Antibodies, Viral - immunology / Antibodies, Viral - metabolism / B-Lymphocytes - virology / BASIC BIOLOGICAL SCIENCES / Cell surface / Chlorocebus aethiops / Computer Simulation / Crystal structure / Crystallography, X-Ray / Disease prevention / Drug Development / Fusion protein / Glycoproteins / HEK293 Cells / HeLa Cells / Humanities and Social Sciences / Humans / Models, Molecular / multidisciplinary / Protein Multimerization - physiology / Proteins / Respiratory syncytial virus / Respiratory Syncytial Virus Infections - immunology / Respiratory Syncytial Virus Infections - prevention & control / Respiratory Syncytial Virus Infections - virology / Respiratory Syncytial Virus Vaccines - immunology / Respiratory Syncytial Virus, Human - isolation & purification / Respiratory Syncytial Virus, Human - physiology / Science / Science (multidisciplinary) / Trimers / Vaccine development / Vero Cells / Viral Fusion Proteins - chemistry / Viral Fusion Proteins - immunology / Viral Fusion Proteins - metabolism / viral infection / viral membrane fusion / Viruses / x-ray crystallography