Publication Abstract from PubMed
Respiratory syncytial virus (RSV) invades host cells via a type I fusion (F) glycoprotein that undergoes dramatic structural rearrangements during the fusion process. Neutralizing monoclonal antibodies such as 101F, palivizumab, and motavizumab, target two major antigenic sites on the RSV F glycoprotein. Structures of these sites as peptide complexes with motavizumab and 101F have been previously determined, but a structure of the trimeric RSV F glycoprotein ectodomain has remained elusive. To address this issue, we undertook structural and biophysical studies on stable ectodomain constructs. Here we present the 2.8 A crystal structure of the trimeric RSV F ectodomain in its post-fusion conformation. The structure revealed that the 101F and motavizumab epitopes are present in the post-fusion state, and that their conformations are similar to those observed in the antibody-bound peptide structures. Both antibodies bound the post-fusion F glycoprotein with high affinity in surface plasmon resonance experiments. Modeling of the antibodies bound to the F glycoprotein predicts that the 101F epitope is larger than the linear peptide and restricted to a single protomer in the trimer, whereas motavizumab likely contacts residues on two protomers, indicating a quaternary epitope. Mechanistically, these results suggest that 101F and motavizumab can bind to multiple conformations of the fusion glycoprotein, and neutralize late in the fusion process. The structural preservation of neutralizing epitopes in the post-fusion state suggests that this conformation can elicit neutralizing antibodies and serve as a useful vaccine antigen.
Structure of the Respiratory Syncytial Virus Fusion Glycoprotein in the Post-fusion Conformation Reveals Preservation of Neutralizing Epitopes.,McLellan JS, Yang Y, Graham BS, Kwong PD J Virol. 2011 May 25. PMID:21613394[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
